@article{%a1.%Y,

title = {Desmin and Plectin Recruitment to the Nucleus and Nuclei Orientation Are Lost in Emery-Dreifuss Muscular Dystrophy Myoblasts Subjected to Mechanical Stimulation},

author = {Cenni V and Evangelisti C and Santi S and Sabatelli P and Neri S and Cavallo M and Lattanzi G and Mattioli E},

url = {https://www.mdpi.com/2073-4409/13/2/162},

doi = {10.3390/cells13020162},

year  = {2024},

date = {2024-01-31},

journal = {Cells},

volume = {13},

issue = {2},

pages = {162},

abstract = {n muscle cells subjected to mechanical stimulation, LINC complex and cytoskeletal proteins are basic to preserve cellular architecture and maintain nuclei orientation and positioning. In this context, the role of lamin A/C remains mostly elusive. This study demonstrates that in human myoblasts subjected to mechanical stretching, lamin A/C recruits desmin and plectin to the nuclear periphery, allowing a proper spatial orientation of the nuclei. Interestingly, in Emery-Dreifuss Muscular Dystrophy (EDMD2) myoblasts exposed to mechanical stretching, the recruitment of desmin and plectin to the nucleus and nuclear orientation were impaired, suggesting that a functional lamin A/C is crucial for the response to mechanical strain. While describing a new mechanism of action headed by lamin A/C, these findings show a structural alteration that could be involved in the onset of the muscle defects observed in muscular laminopathies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_148,

title = {Proceedings of the annual meeting of the European Consortium of Lipodystrophies (ECLip), Pisa, Italy, 28-29 September 2023.},

author = {Ceccarini G and Akinci B and Araujo-Vilar D and Beghini M and Brown RJ and Tudela JC and Corradin V and Donadille B and Ruiz JJ and Jeru I and Lattanzi G and Maffei M and McIlroy GD and Nobécourt E and Perez de Tudela N and Rochford J and Sanders R and Schnurbein JV and Tews D and Vantyghem MC and Vatier C and Vigouroux C and Santini F.},

url = {https://www.sciencedirect.com/science/article/pii/S0003426624000362?via%3Dihub},

doi = {10.1016/j.ando.2024.03.002},

year  = {2024},

date = {2024-03-18},

journal = {Annales d'endocrinologie},

abstract = {Lipodystrophic syndromes are rare diseases affecting primarily the development or maintenance of the adipose tissue but are also distressing indirectly multiple organs and tissues, causing in most of the cases reduced life expectancy and quality of life. Lipodystrophy syndromes are multifaceted disorders caused by genetic mutations or autoimmune and iatrogenic mechanisms, many subtypes are now recognized and classified but the disease remains remarkably underdiagnosed. The European Consortium of Lipodystrophies (ECLip) was founded in 2014 as a non-profit network of European centers of excellence working in the field of lipodystrophies aiming at promoting international collaborations to increase basic scientific understanding and clinical management of these syndromes. The network has developed a European Patient Registry as a collaborative research platform for consortium members. ECLip and ECLip registry activities involve patient advocacy groups to increase public awareness and to advice on research activities relevant from the patients perspective. The annual ECLip congress gives an update on the research results of the various network groups members.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{%a1.%Y_126,

title = {Clinical and functional characterization of COL2A1 p.Gly444Ser variant: From a fetal phenotype to a previously undisclosed postnatal phenotype},

author = {Marchionni E and D'Apice MR and Lupo V and Lattanzi G and Mattioli E and Lisignoli G and Gabusi E and Pepe G and Helmer Citterich M and Campione E and Nardone AM and Spitalieri P and Pucci N and Cocciadiferro D and Picchi E and Garaci F and Novelli A and Novelli G.},

url = {https://www.sciencedirect.com/science/article/pii/S2352187223000748?via%3Dihub},

doi = {10.1016/j.bonr.2023.101728},

year  = {2023},

date = {2023-02-23},

journal = {Bone reports},

volume = {19},

pages = {101728},

abstract = {COL2A1 gene encodes the alpha-1 chain of type-II procollagen. Heterozygous pathogenic variants are associated with the broad clinical spectrum of genetic diseases known as type-II collagenopathies. We aimed to characterize the NM_001844.5:c.1330G>A;p.Gly444Ser variant detected in the COL2A1 gene through trio-based prenatal exome sequencing in a fetus presenting a severe skeletal phenotype at 31 Gestational Weeks and in his previously undisclosed mild-affected father. Functional studies on father's cutaneous fibroblasts, along with in silico protein modeling and in vitro chondrocytes differentiation, showed intracellular accumulation of collagen-II, its localization in external Golgi vesicles and nuclear morphological alterations. Extracellular matrix showed a disorganized fibronectin network. These results showed that p.Gly444Ser variant alters procollagen molecules processing and the assembly of mature type-II collagen fibrils, according to COL2A1-chain disorganization, displayed by protein modeling. Clinical assessment at 38 y.o., through a reverse-phenotyping approach, revealed limp gait, short and stocky appearance. X-Ray and MRI showed pelvis asymmetry with severe morpho-structural alterations of the femoral heads bilaterally, consistent with a mild form of type-II collagenopathy. This study shows how the fusion of genomics and clinical expertise can drive a diagnosis supported by cellular and bioinformatics studies to effectively establish variants pathogenicity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_117,

title = {Epigenomic signature of accelerated ageing in progeroid Cockayne syndrome},

author = {Crochemore C and Chica C and Garagnani P and Lattanzi G and Horvath S and Sarasin A and Franceschi C and Bacalini MG and Ricchetti M},

url = {https://onlinelibrary.wiley.com/doi/10.1111/acel.13959},

doi = {10.1111/acel.13959},

year  = {2023},

date = {2023-10-05},

urldate = {2023-10-05},

journal = {Aging Cell},

volume = {22},

issue = {10},

pages = {e13959},

abstract = {Cockayne syndrome (CS) and UV-sensitive syndrome (UVSS) are rare genetic disorders caused by mutation of the DNA repair and multifunctional CSA or CSB protein, but only CS patients display a progeroid and neurodegenerative phenotype, providing a unique conceptual and experimental paradigm. As DNA methylation (DNAm) remodelling is a major ageing marker, we performed genome-wide analysis of DNAm of fibroblasts from healthy, UVSS and CS individuals. Differential analysis highlighted a CS-specific epigenomic signature (progeroid-related; not present in UVSS) enriched in three categories: developmental transcription factors, ion/neurotransmitter membrane transporters and synaptic neuro-developmental genes. A large fraction of CS-specific DNAm changes were associated with expression changes in CS samples, including in previously reported post-mortem cerebella. The progeroid phenotype of CS was further supported by epigenomic hallmarks of ageing: the prediction of DNAm of repetitive elements suggested an hypomethylation of Alu sequences in CS, and the epigenetic clock returned a marked increase in CS biological age respect to healthy and UVSS cells. The epigenomic remodelling of accelerated ageing in CS displayed both commonalities and differences with other progeroid diseases and regular ageing. CS shared DNAm changes with normal ageing more than other progeroid diseases do, and included genes functionally validated for regular ageing. Collectively, our results support the existence of an epigenomic basis of accelerated ageing in CS and unveil new genes and pathways that are potentially associated with the progeroid/degenerative phenotype.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_115,

title = {Impact of Combined Baricitinib and FTI Treatment on Adipogenesis in Hutchinson-Gilford Progeria Syndrome and Other Lipodystrophic Laminopathies},

author = {Hartinger R and Lederer EM and Schena E and Lattanzi G and Djabali K},

url = {https://www.mdpi.com/2073-4409/12/10/1350},

doi = {10.3390/cells12101350},

year  = {2023},

date = {2023-08-08},

journal = {Cells},

volume = {12},

issue = {10},

pages = {1350},

abstract = {Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease that causes premature aging symptoms, such as vascular diseases, lipodystrophy, loss of bone mineral density, and alopecia. HGPS is mostly linked to a heterozygous and de novo mutation in the LMNA gene (c.1824 C > T; p.G608G), resulting in the production of a truncated prelamin A protein called "progerin". Progerin accumulation causes nuclear dysfunction, premature senescence, and apoptosis. Here, we examined the effects of baricitinib (Bar), an FDA-approved JAK/STAT inhibitor, and a combination of Bar and lonafarnib (FTI) treatment on adipogenesis using skin-derived precursors (SKPs). We analyzed the effect of these treatments on the differentiation potential of SKPs isolated from pre-established human primary fibroblast cultures. Compared to mock-treated HGPS SKPs, Bar and Bar + FTI treatments improved the differentiation of HGPS SKPs into adipocytes and lipid droplet formation. Similarly, Bar and Bar + FTI treatments improved the differentiation of SKPs derived from patients with two other lipodystrophic diseases: familial partial lipodystrophy type 2 (FPLD2) and mandibuloacral dysplasia type B (MADB). Overall, the results show that Bar treatment improves adipogenesis and lipid droplet formation in HGPS, FPLD2, and MADB, indicating that Bar + FTI treatment might further ameliorate HGPS pathologies compared to lonafarnib treatment alone.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_132,

title = {Mineralocorticoid Receptor Antagonism Prevents Type 2 Familial Partial Lipodystrophy Brown Adipocyte Dysfunction},

author = {Schena E and Mattioli E and Peres C and Zanotti L and Morselli P and Iozzo P and Guzzardi MA and Bernardini C and Forni M and Nesci S and Caprio M and Cecchetti C and Pagotto U and Gabusi E and Cattini L and Lisignoli G and Blalock WL and Gambineri A and Lattanzi G},

url = {https://www.mdpi.com/2073-4409/12/22/2586},

doi = {10.3390/cells12222586},

year  = {2023},

date = {2023-10-10},

urldate = {2023-10-10},

journal = {CELLS},

volume = {12},

issue = {22},

pages = {2586},

abstract = {Type-2 Familial Partial Lipodystrophy (FPLD2), a rare lipodystrophy caused by LMNA mutations, is characterized by a loss of subcutaneous fat from the trunk and limbs and excess accumulation of adipose tissue in the neck and face. Several studies have reported that the mineralocorticoid receptor (MR) plays an essential role in adipose tissue differentiation and functionality. We previously showed that brown preadipocytes isolated from a FPLD2 patient's neck aberrantly differentiate towards the white lineage. As this condition may be related to MR activation, we suspected altered MR dynamics in FPLD2. Despite cytoplasmic MR localization in control brown adipocytes, retention of MR was observed in FPLD2 brown adipocyte nuclei. Moreover, overexpression of wild-type or mutated prelamin A caused GFP-MR recruitment to the nuclear envelope in HEK293 cells, while drug-induced prelamin A co-localized with endogenous MR in human preadipocytes. Based on in silico analysis and in situ protein ligation assays, we could suggest an interaction between prelamin A and MR, which appears to be inhibited by mineralocorticoid receptor antagonism. Importantly, the MR antagonist spironolactone redirected FPLD2 preadipocyte differentiation towards the brown lineage, avoiding the formation of enlarged and dysmorphic lipid droplets. Finally, beneficial effects on brown adipose tissue activity were observed in an FPLD2 patient undergoing spironolactone treatment. These findings identify MR as a new lamin A interactor and a new player in lamin A-linked lipodystrophies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_31,

title = {A Single mtDNA Deletion in Association with a LMNA Gene New Frameshift Variant: A Case Report},

author = {Montano V and Mancuso M and Simoncini C and Torri F and Chico L and Ali G and Rocchi A and Baldinotti F and Caligo MA and Lattanzi G and Mattioli E and Cenacchi G and Barison A and Siciliano G and Ricci G},

url = {https://content.iospress.com/articles/journal-of-neuromuscular-diseases/jnd220802},

doi = {10.3233/JND-220802},

year  = {2022},

date = {2022-08-25},

journal = {Journal of neuromuscular diseases},

volume = {9},

issue = {3457-462},

abstract = {Background: Proximal muscle weakness may be the presenting clinical feature of different types of myopathies, including limb girdle muscular dystrophy and primary mitochondrial myopathy. LGMD1B is caused by LMNA mutation. It is characterized by progressive weakness and wasting leading to proximal weakness, cardiomyopathy, and hearth conduction block. Objective: In this article, we describe the case of a patient who presented with limb-girdle weakness and a double trouble scenario -mitochondrial DNA single deletion and a new LMNA mutation. Methods: Pathophysiological aspects were investigated with muscle biopsy, Western Blot analysis, NGS nuclear and mtDNA analysis and neuromuscular imaging (muscle and cardiac MRI). Results: Although secondary mitochondrial involvement is possible, a "double trouble" syndrome can not be excluded. Conclusion: Implication deriving from hypothetical coexistence of two different pathological conditions or the possible secondary mitochondrial involvement are discussed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_40,

title = {Clinical Profile, Arrhythmias, and Adverse Cardiac Outcomes in Emery-Dreifuss Muscular Dystrophies: A Systematic Review of the Literature},

author = {Valenti AC and Albini A and Imberti JF and Vitolo M and Bonini N and Lattanzi G and Schnabel RB and Boriani G},

url = {https://www.mdpi.com/2079-7737/11/4/530},

doi = { doi: 10.3390/biology11040530},

year  = {2022},

date = {2022-08-18},

journal = {Biology (Basel)},

volume = {11},

issue = {4},

abstract = {Cardiolaminopathies are a heterogeneous group of disorders which are due to mutations in the genes encoding for nuclear lamins or their binding proteins. The whole spectrum of cardiac manifestations encompasses atrial arrhythmias, conduction disturbances, progressive systolic dysfunction, and malignant ventricular arrhythmias. Despite the prognostic significance of cardiac involvement in this setting, the current recommendations lack strong evidence. The aim of our work was to systematically review the current data on the main cardiovascular outcomes in cardiolaminopathies. We searched PubMed/Embase for studies focusing on cardiovascular outcomes in LMNA mutation carriers (atrial arrhythmias, ventricular arrhythmias, sudden cardiac death, conduction disturbances, thromboembolic events, systolic dysfunction, heart transplantation, and all-cause and cardiovascular mortality). In total, 11 studies were included (1070 patients, mean age between 26-45 years, with follow-up periods ranging from 2.5 years up to 45 ± 12). When available, data on the EMD-mutated population were separately reported (40 patients). The incidence rates (IR) were individually assessed for the outcomes of interest. The IR for atrial fibrillation/atrial flutter/atrial tachycardia ranged between 6.1 and 13.9 events/100 pts-year. The IR of atrial standstill ranged between 0 and 2 events/100 pts-year. The IR for malignant ventricular arrhythmias reached 10.2 events/100 pts-year and 15.6 events/100 pts-year for appropriate implantable cardioverter-defibrillator (ICD) interventions. The IR for advanced conduction disturbances ranged between 3.2 and 7.7 events/100 pts-year. The IR of thromboembolic events reached up to 8.9 events/100 pts-year. Our results strengthen the need for periodic cardiological evaluation focusing on the early recognition of atrial arrhythmias, and possibly for the choice of preventive strategies for thromboembolic events. The frequent need for cardiac pacing due to advanced conduction disturbances should be counterbalanced with the high risk of malignant ventricular arrhythmias that would justify ICD over pacemaker implantation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybd,

title = {Genomic loci mispositioning in Tmem120a knockout mice yields latent lipodystrophy},

author = {Czapiewski R and Batrakou DG and de Las Heras JI and Carter RN and Sivakumar A and Sliwinska M and Dixon CR and Webb S and Lattanzi G and Morton NM and Schirmer EC},

url = {https://www.nature.com/articles/s41467-021-27869-2},

doi = {10.1038/s41467-021-27869-2},

year  = {2022},

date = {2022-02-25},

urldate = {2022-02-25},

journal = {Nature communications},

volume = {13},

number = {321},

issue = {1},

abstract = {Little is known about how the observed fat-specific pattern of 3D-spatial genome organisation is established. Here we report that adipocyte-specific knockout of the gene encoding nuclear envelope transmembrane protein Tmem120a disrupts fat genome organisation, thus causing a lipodystrophy syndrome. Tmem120a deficiency broadly suppresses lipid metabolism pathway gene expression and induces myogenic gene expression by repositioning genes, enhancers and miRNA-encoding loci between the nuclear periphery and interior. Tmem120a-/- mice, particularly females, exhibit a lipodystrophy syndrome similar to human familial partial lipodystrophy FPLD2, with profound insulin resistance and metabolic defects that manifest upon exposure to an obesogenic diet. Interestingly, similar genome organisation defects occurred in cells from FPLD2 patients that harbour nuclear envelope protein encoding LMNA mutations. Our data indicate TMEM120A genome organisation functions affect many adipose functions and its loss may yield adiposity spectrum disorders, including a miRNA-based mechanism that could explain muscle hypertrophy in human lipodystrophy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybr,

title = {Lamin A and the LINC complex act as potential tumor suppressors in Ewing Sarcoma},

author = {Chiarini F and Paganelli F and Balestra T and Capanni C and Fazio A and Manara MC and Landuzzi L and Petrini S and Evangelisti C and Lollini PL and Martelli AM and Lattanzi G and Scotlandi K},

url = {https://www.nature.com/articles/s41419-022-04729-5},

doi = {10.1038/s41419-022-04729-5},

year  = {2022},

date = {2022-05-30},

urldate = {2022-05-30},

journal = {Cell death & disease},

volume = {13},

issue = {4},

pages = {346},

abstract = {Lamin A, a main constituent of the nuclear lamina, is involved in mechanosignaling and cell migration through dynamic interactions with the LINC complex, formed by the nuclear envelope proteins SUN1, SUN2 and the nesprins. Here, we investigated lamin A role in Ewing Sarcoma (EWS), an aggressive bone tumor affecting children and young adults. In patients affected by EWS, we found a significant inverse correlation between LMNA gene expression and tumor aggressiveness. Accordingly, in experimental in vitro models, low lamin A expression correlated with enhanced cell migration and invasiveness and, in vivo, with an increased metastatic load. At the molecular level, this condition was linked to altered expression and anchorage of nuclear envelope proteins and increased nuclear retention of YAP/TAZ, a mechanosignaling effector. Conversely, overexpression of lamin A rescued LINC complex organization, thus reducing YAP/TAZ nuclear recruitment and preventing cell invasiveness. These effects were also obtained through modulation of lamin A maturation by a statin-based pharmacological treatment that further elicited a more differentiated phenotype in EWS cells. These results demonstrate that drugs inducing nuclear envelope remodeling could be exploited to improve therapeutic strategies for EWS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y__500,

title = {Ectopic Expression of Ankrd2 Affects Proliferation, Motility and Clonogenic Potential of Human Osteosarcoma Cells. },

author = {Piazzi M and Kojic S and Capanni C and Stamenkovic N and Bavelloni A and Marin O and Lattanzi G and Blalock WL and Cenni V},

url = {https://www.mdpi.com/2072-6694/13/2/174},

doi = {10.3390/cancers13020174},

year  = {2021},

date = {2021-03-09},

urldate = {2021-03-09},

journal = {Cancers (Basel)},

volume = {13},

number = {2},

pages = {e174},

abstract = {Ankrd2 is a protein known for being mainly expressed in muscle fibers, where it participates in the mechanical stress response. Since both myocytes and osteoblasts are mesenchymal-derived cells, we were interested in examining the role of Ankrd2 in the progression of osteosarcoma which features a mechano-stress component. Although having been identified in many tumor-derived cell lines and -tissues, no study has yet described nor hypothesized any involvement for this protein in osteosarcoma tumorigenesis. In this paper, we report that Ankrd2 is expressed in cell lines obtained from human osteosarcoma and demonstrate a contribution by this protein in the pathogenesis of this insidious disease. Ankrd2 involvement in osteosarcoma development was evaluated in clones of Saos2, U2OS, HOS and MG63 cells stably expressing Ankrd2, through the investigation of hallmark processes of cancer cells. Interestingly, we found that exogenous expression of Ankrd2 influenced cellular growth, migration and clonogenicity in a cell line-dependent manner, whereas it was able to improve the formation of 3D spheroids in three out of four cellular models and enhanced matrix metalloproteinase (MMP) activity in all tested cell lines. Conversely, downregulation of Ankrd2 expression remarkably reduced proliferation and clonogenic potential of parental cells. As a whole, our data present Ankrd2 as a novel player in osteosarcoma development, opening up new therapeutic perspectives.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y__504,

title = {Interleukin-6 neutralization ameliorates symptoms in prematurely aged mice.},

author = {Squarzoni S and Schena E and Sabatelli P and Mattioli E and Capanni C and Cenni V and D'Apice MR and Andrenacci D and Sarli G and Pellegrino V and Festa A and Baruffaldi F and

Storci G and Bonafè M and Barboni C and Sanapo M and Zaghini A and Lattanzi G},

url = {https://onlinelibrary.wiley.com/doi/10.1111/acel.13285},

doi = {10.1111/acel.13285},

year  = {2021},

date = {2021-03-09},

urldate = {2021-03-09},

journal = {Aging Cell},

volume = {20},

number = {1},

pages = {e13285},

abstract = {Hutchinson-Gilford progeria syndrome (HGPS) causes premature aging in children, with adipose tissue, skin and bone deterioration, and cardiovascular impairment. In HGPS cells and mouse models, high levels of interleukin-6, an inflammatory cytokine linked to aging processes, have been detected. Here, we show that inhibition of interleukin-6 activity by tocilizumab, a neutralizing antibody raised against interleukin-6 receptors, counteracts progeroid features in both HGPS fibroblasts and LmnaG609G / G609G progeroid mice. Tocilizumab treatment limits the accumulation of progerin, the toxic protein produced in HGPS cells, rescues nuclear envelope and chromatin abnormalities, and attenuates the hyperactivated DNA damage response. In vivo administration of tocilizumab reduces aortic lesions and adipose tissue dystrophy, delays the onset of lipodystrophy and kyphosis, avoids motor impairment, and preserves a good quality of life in progeroid mice. This work identifies tocilizumab as a valuable tool in HGPS therapy and, speculatively, in the treatment of a variety of aging-related disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y__507,

title = {Joining European Scientific Forces to Face Pandemics. },

author = {Vasconcelos MH and Alcaro S and Arechavala-Gomeza V and Baumbach J and Borges F and Brevini TAL and Rivas JL and Devaux Y and Hozak P and Keinanen-Toivola MM and Lattanzi G and Mohr T and Murovska M and Prusty BK and Quinlan RA and Perez-Sala D and Scheibenbogen C and Schmidt HHHW and Silveira I and Tieri P and Tolios A and Riganti C},

url = {https://www.sciencedirect.com/science/article/pii/S0966842X20302705?via%3Dihub},

doi = {10.1016/j.tim.2020.10.008},

year  = {2021},

date = {2021-03-09},

journal = {Trends in microbiology},

volume = {29},

number = {2},

pages = {92-97},

abstract = {Despite the international guidelines on the containment of the coronavirus disease 2019 (COVID-19) pandemic, the European scientific community was not sufficiently prepared to coordinate scientific efforts. To improve preparedness for future pandemics, we have initiated a network of nine European-funded Cooperation in Science and Technology (COST) Actions that can help facilitate inter-, multi-, and trans-disciplinary communication and collaboration.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y__494,

title = {Morphological study of TNPO3 and SRSF1 interaction during myogenesis by combining confocal, structured illumination and electron microscopy analysis. },

author = {Costa R and Rodia MT and Zini N and Pegoraro V and Marozzo R and Capanni C and Angelini C and Lattanzi G and Santi S and Cenacchi G},

url = {https://link.springer.com/article/10.1007/s11010-020-04023-y},

doi = {10.1007/s11010-020-04023-y},

year  = {2021},

date = {2021-03-09},

urldate = {2021-03-09},

journal = {Molecular and cellular biochemistry},

volume = {476},

number = {4},

pages = {1797-1811},

abstract = {Transportin3 (TNPO3) shuttles the SR proteins from the cytoplasm to the nucleus. The SR family includes essential splicing factors, such as SRSF1, that influence alternative splicing, controlling protein diversity in muscle and satellite cell differentiation. Given the importance of alternative splicing in the myogenic process and in the maintenance of healthy muscle, alterations in the splicing mechanism might contribute to the development of muscle disorders. Combining confocal, structured illumination and electron microscopy, we investigated the expression of TNPO3 and SRSF1 during myogenesis, looking at nuclear and cytoplasmic compartments. We investigated TNPO3 and its interaction with SRSF1 and we observed that SRSF1 remained mainly localized in the nucleus, while TNPO3 decreased in the cytoplasm and was strongly clustered in the nuclei of differentiated myotubes. In conclusion, combining different imaging techniques led us to describe the behavior of TNPO3 and SRSF1 during myogenesis, showing that their dynamics follow the myogenic process and could influence the proteomic network necessary during myogenesis. The combination of different high-, super- and ultra-resolution imaging techniques led us to describe the behavior of TNPO3 and its interaction with SRSF1, looking at nuclear and cytoplasmic compartments. These observations represent a first step in understanding the role of TNPO3 and SRFSF1 in complex mechanisms, such as myogenesis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Yb_71,

title = {Retrotransposons Down- and Up-Regulation in Aging Somatic Tissue},

author = {Giordani G and Cavaliere V and Gargiulo G and Lattanzi G and Andrenacci D},

url = {https://www.mdpi.com/2073-4409/11/1/79},

doi = {10.3390/cells11010079},

year  = {2021},

date = {2021-12-30},

journal = {Cells},

volume = {11},

number = {1},

pages = {79},

abstract = {The transposon theory of aging hypothesizes the activation of transposable elements (TEs) in somatic tissues with age, leading to a shortening of the lifespan. It is thought that TE activation in aging produces an increase in DNA double-strand breaks, contributing to genome instability and promoting the activation of inflammatory responses. To investigate how TE regulation changes in somatic tissues during aging, we analyzed the expression of some TEs, as well as a source of small RNAs that specifically silence the analyzed TEs; the Drosophila cluster named flamenco. We found significant variations in the expression levels of all the analyzed TEs during aging, with a trend toward reduction in middle-aged adults and reactivation in older individuals that suggests dynamic regulation during the lifespan.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_432,

title = {Cytokine Profile in Striated Muscle Laminopathies: New Promising Biomarkers for Disease Prediction},

author = {Cappelletti C and Tramacere I and Cavalcante P and Schena E and Politano L and Carboni N and Gambineri A and {D'Amico A} and Ruggiero L and Ricci G and Siciliano G and Boriani G and Mongini TE and Vercelli L and Biagini E and Ziacchi M and {D'Apice MR} and Lattanzi G and Mantegazza R and Maggi L and Bernasconi P},

url = {https://www.mdpi.com/2073-4409/9/6/1532},

doi = {10.3390/cells9061532},

year  = {2020},

date = {2020-01-01},

journal = {Cells},

volume = {9},

number = {6},

pages = {1532},

abstract = {Laminopathies are a wide and heterogeneous group of rare human diseases caused by mutations of the LMNA gene or related nuclear envelope genes. The variety of clinical phenotypes and the wide spectrum of histopathological changes among patients carrying an identical mutation in the LMNA gene make the prognostic process rather difficult, and classical genetic screens appear to have limited predictive value for disease development. The aim of this study was to evaluate whether a comprehensive profile of circulating cytokines may be a useful tool to differentiate and stratify disease subgroups, support clinical follow-ups and contribute to new therapeutic approaches. Serum levels of 51 pro- and anti-inflammatory molecules, including cytokines, chemokines and growth factors, were quantified by a Luminex multiple immune-assay in 53 patients with muscular laminopathy (Musc-LMNA), 10 with non-muscular laminopathy, 22 with other muscular disorders and in 35 healthy controls. Interleukin-17 (IL-17), granulocyte colony-stimulating factor (G-CSF) and transforming growth factor beta (TGF-β2) levels significantly discriminated Musc-LMNA from controls; interleukin-1β (IL-1β), interleukin-4 (IL-4) and interleukin-8 (IL-8) were differentially expressed in Musc-LMNA patients compared to those with non-muscular laminopathies, whereas IL-17 was significantly higher in Musc-LMNA patients with muscular and cardiac involvement. These findings support the hypothesis of a key role of the immune system in Musc-LMNA and emphasize the potential use of cytokines as biomarkers for these disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_436,

title = {Emerin Phosphorylation during the Early Phase of the Oxidative Stress Response Influences Emerin-BAF Interaction and BAF Nuclear Localization},

author = {Cenni V and Squarzoni S and Loi M and Mattioli E and Lattanzi G and Capanni C},

url = {https://www.mdpi.com/2073-4409/9/6/1415},

doi = {10.3390/cells9061415},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Cells},

volume = {9},

number = {6},

pages = {1415},

abstract = {Reactive Oxygen Species (ROS) are reactive molecules required for the maintenance of physiological functions. Oxidative stress arises when ROS production exceeds the cellular ability to eliminate such molecules. In this study, we showed that oxidative stress induces post-translational modification of the inner nuclear membrane protein emerin. In particular, emerin is phosphorylated at the early stages of the oxidative stress response, while protein phosphorylation is abolished upon recovery from stress. A finely tuned balance between emerin phosphorylation and O-GlcNAcylation seems to govern this dynamic and modulates emerin-BAF interaction and BAF nucleoplasmic localization during the oxidative stress response. Interestingly, emerin post-translational modifications, similar to those observed during the stress response, are detected in cells bearing LMNA gene mutations and are characterized by a free radical generating environment. On the other hand, under oxidative stress conditions, a delay in DNA damage repair and cell cycle progression is found in cells from Emery-Dreifuss Muscular Dystrophy type 1, which do not express emerin. These results suggest a role of the emerin-BAF protein platform in the DNA damage response aimed at counteracting the detrimental effects of elevated levels of ROS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_482,

title = {European lipodystrophy registry: background and structure.},

author = {{von Schnurbein J} and Adams C and Akinci B and Ceccarini G and {D'Apice MR} and Gambineri A and Hennekam RCM and Jeru I and Lattanzi G and Miehle K and Nagel G and Novelli G and Santini F and {Santos Silva E} and Savage DB and Sbraccia P and Schaaf J and Sorkina E and Tanteles G and Vantyghem MC and Vatier C and Vigouroux C and Vorona E and Araujo-Vilar D and Wabitsch M},

url = {https://ojrd.biomedcentral.com/articles/10.1186/s13023-020-1295-y},

doi = {10.1186/s13023-020-1295-y},

year  = {2020},

date = {2020-01-01},

journal = {Orphanet journal of rare diseases},

volume = {15},

number = {1},

pages = {17},

abstract = {BACKGROUND: Lipodystrophy syndromes comprise a group of extremely rare and heterogeneous diseases characterized by a selective loss of adipose tissue in the absence of nutritional deprivation or catabolic state. Because of the rarity of each lipodystrophy subform, research in this area is difficult and international co-operation mandatory. Therefore, in 2016, the European Consortium of Lipodystrophies (ECLip) decided to create a registry for patients with lipodystrophy. RESULTS: The registry was build using the information technology Open Source Registry System for Rare Diseases in the EU (OSSE), an open-source software and toolbox. Lipodystrophy specific data forms were developed based on current knowledge of typical signs and symptoms of lipodystrophy. The platform complies with the new General Data Protection Regulation (EU) 2016/679 by ensuring patient pseudonymization, informational separation of powers, secure data storage and security of communication, user authentication, person specific access to data, and recording of access granted to any data. Inclusion criteria are all patients with any form of lipodystrophy (with the exception of HIV-associated lipodystrophy). So far 246 patients from nine centres (Amsterdam, Bologna, Izmir, Leipzig, Münster, Moscow, Pisa, Santiago de Compostela, Ulm) have been recruited. With the help from the six centres on the brink of recruitment (Cambridge, Lille, Nicosia, Paris, Porto, Rome) this number is expected to double within the next one or 2 years. CONCLUSIONS: A European registry for all patients with lipodystrophy will provide a platform for improved research in the area of lipodystrophy. All physicians from Europe and neighbouring countries caring for patients with lipodystrophy are invited to participate in the ECLip Registry. STUDY REGISTRATION:ClinicalTrials.gov (NCT03553420). Registered 14 March 2018, retrospectively registered.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_99,

title = {European lipodystrophy registry: background and structure.},

author = {{von Schnurbein J} and Adams C and Akinci B and Ceccarini G and D'Apice MR and Gambineri A and Hennekam RCM and Jeru I and Lattanzi G and Miehle K and Nagel G and Novelli G and Santini F and Santos Silva E and Savage DB and Sbraccia P and Schaaf J and Sorkina E and Tanteles G and Vantyghem MC and Vatier C and Vigouroux C and Vorona E and Araújo-Vilar D and Wabitsch M},

url = {https://ojrd.biomedcentral.com/articles/10.1186/s13023-020-1295-y},

doi = {10.1186/s13023-020-1295-y},

year  = {2020},

date = {2020-02-13},

journal = {Orphanet journal of rare diseases},

volume = {15},

number = {1},

pages = {17},

abstract = {BACKGROUND: Lipodystrophy syndromes comprise a group of extremely rare and heterogeneous diseases characterized by a selective loss of adipose tissue in the absence of nutritional deprivation or catabolic state. Because of the rarity of each lipodystrophy subform, research in this area is difficult and international co-operation mandatory. Therefore, in 2016, the European Consortium of Lipodystrophies (ECLip) decided to create a registry for patients with lipodystrophy. RESULTS: The registry was build using the information technology Open Source Registry System for Rare Diseases in the EU (OSSE), an open-source software and toolbox. Lipodystrophy specific data forms were developed based on current knowledge of typical signs and symptoms of lipodystrophy. The platform complies with the new General Data Protection Regulation (EU) 2016/679 by ensuring patient pseudonymization, informational separation of powers, secure data storage and security of communication, user authentication, person specific access to data, and recording of access granted to any data. Inclusion criteria are all patients with any form of lipodystrophy (with the exception of HIV-associated lipodystrophy). So far 246 patients from nine centres (Amsterdam, Bologna, Izmir, Leipzig, Münster, Moscow, Pisa, Santiago de Compostela, Ulm) have been recruited. With the help from the six centres on the brink of recruitment (Cambridge, Lille, Nicosia, Paris, Porto, Rome) this number is expected to double within the next one or 2 years. CONCLUSIONS: A European registry for all patients with lipodystrophy will provide a platform for improved research in the area of lipodystrophy. All physicians from Europe and neighbouring countries caring for patients with lipodystrophy are invited to participate in the ECLip Registry. STUDY REGISTRATION:ClinicalTrials.gov (NCT03553420). Registered 14 March 2018, retrospectively registered.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_481,

title = {Joining European Scientific Forces to Face Pandemics.},

author = {Vasconcelos MH and Alcaro S and Arechavala-Gomeza V and Baumbach J and Borges F and Brevini TAL and Rivas JL and Devaux Y and Hozak P and Keinanen-Toivola MM and Lattanzi G and Mohr T and Murovska M and Prusty BK and Quinlan RA and Perez-Sala D and Scheibenbogen C and Schmidt HHHW and Silveira I and Tieri P and Tolios A and Riganti C},

url = {https://www.cell.com/trends/microbiology/fulltext/S0966-842X(20)30270-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0966842X20302705%3Fshowall%3Dtrue},

doi = {10.1016/j.tim.2020.10.008},

year  = {2020},

date = {2020-01-01},

journal = {Trends in microbiology},

volume = {S0966-842X(20)},

pages = {30270-30275},

abstract = {Despite the international guidelines on the containment of the coronavirus disease 2019 (COVID-19) pandemic, the European scientific community was not sufficiently prepared to coordinate scientific efforts. To improve preparedness for future pandemics, we have initiated a network of nine European-funded Cooperation in Science and Technology (COST) Actions that can help facilitate inter-, multi-, and trans-disciplinary communication and collaboration.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_449,

title = {Lamin A and Prelamin A Counteract Migration of Osteosarcoma Cells},

author = {Evangelisti C and Paganelli F and Giuntini G and Mattioli E and Cappellini A and Ramazzotti G and Faenza I and Maltarello MC and Martelli AM and Scotlandi K and Chiarini F and Lattanzi G},

url = {https://www.mdpi.com/2073-4409/9/3/774},

doi = {10.3390/cells9030774},

year  = {2020},

date = {2020-01-01},

journal = {Cells},

volume = {9},

number = {3},

pages = {774},

abstract = {A type lamins are fundamental components of the nuclear lamina. Changes in lamin A expression correlate with malignant transformation in several cancers. However, the role of lamin A has not been explored in osteosarcoma (OS). Here, we wanted to investigate the role of lamin A in normal osteoblasts (OBs) and OS cells. Thus, we studied the expression of lamin A/C in OS cells compared to OBs and evaluated the effects of lamin A overexpression in OS cell lines. We show that, while lamin A expression increases during osteoblast differentiation, all examined OS cell lines express lower lamin A levels relative to differentiated OBs. The condition of low LMNA expression confers to OS cells a significant increase in migration potential, while overexpression of lamin A reduces migration ability of OS cells. Moreover, overexpression of unprocessable prelamin A also reduces cell migration. In agreement with the latter finding, OS cells which accumulate the highest prelamin A levels upon inhibition of lamin A maturation by statins, had significantly reduced migration ability. Importantly, OS cells subjected to statin treatment underwent apoptotic cell death in a RAS-independent, lamin A-dependent manner. Our results show that pro-apoptotic effects of statins and statin inhibitory effect on OS cell migration are comparable to those obtained by prelamin A accumulation and further suggest that modulation of lamin A expression and post-translational processing can be a tool to decrease migration potential in OS cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_435,

title = {Lamin A Involvement in Ageing Processes},

author = {Cenni V and Capanni C and Mattioli E and Schena E and Squarzoni S and Bacalini MG and Garagnani P and Salvioli S and Franceschi C and Lattanzi G},

url = {https://www.sciencedirect.com/science/article/pii/S1568163719302107},

doi = {10.1016/j.arr.2020.101073},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Ageing research reviews},

volume = {62},

pages = {101073},

abstract = {Lamin A, a main constituent of the nuclear lamina, is the major splicing product of the LMNA gene, which also encodes lamin C, lamin A delta 10 and lamin C2. Involvement of lamin A in the ageing process became clear after the discovery that a group of progeroid syndromes, currently referred to as progeroid laminopathies, are caused by mutations in LMNA gene. Progeroid laminopathies include Hutchinson-Gilford Progeria, Mandibuloacral Dysplasia, Atypical Progeria and atypical-Werner syndrome, disabling and life-threatening diseases with accelerated ageing, bone resorption, lipodystrophy, skin abnormalities and cardiovascular disorders. Defects in lamin A post-translational maturation occur in progeroid syndromes and accumulated prelamin A affects ageing-related processes, such as mTOR signaling, epigenetic modifications, stress response, inflammation, microRNA activation and mechanosignaling. In this review, we briefly describe the role of these pathways in physiological ageing and go in deep into lamin A-dependent mechanisms that accelerate the ageing process. Finally, we propose that lamin A acts as a sensor of cell intrinsic and environmental stress through transient prelamin A accumulation, which triggers stress response mechanisms. Exacerbation of lamin A sensor activity due to stably elevated prelamin A levels contributes to the onset of a permanent stress response condition, which triggers accelerated ageing.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_100,

title = {Long term breeding of the Lmna G609G progeric mouse: Characterization of homozygous and heterozygous models.},

author = {Zaghini A and Sarli G and Barboni C and Sanapo M and Pellegrino V and Diana A and Linta N and Rambaldi J and {D'Apice MR} and Murdocca M and Baleani M and Baruffaldi F and Fognani R and Mecca R and Festa A and Papparella S and Paciello O and Prisco F and Capanni C and Loi M and Schena E and Lattanzi G and Squarzoni S},

url = {https://www.sciencedirect.com/science/article/pii/S0531556519304127?via%3Dihub},

doi = { 10.1016/j.exger.2019.110784},

year  = {2020},

date = {2020-03-04},

urldate = {2020-03-04},

journal = {Experimental gerontology},

volume = {130},

pages = {110784},

abstract = {The transgenic LmnaG609G progeric mouse represents an outstanding animal model for studying the human Hutchinson-Gilford Progeria Syndrome (HGPS) caused by a mutation in the LMNA gene, coding for the nuclear envelope protein Lamin A/C, and, as an important, more general scope, for studying the complex process governing physiological aging in humans. Here we give a comprehensive description of the peculiarities related to the breeding of LmnaG609G mice over a prolonged period of time, and of many features observed in a large colony for a 2-years period. We describe the breeding and housing conditions underlining the possible interference of the genetic background on the phenotype expression. This information represents a useful tool when planning and interpreting studies on the LmnaG609G mouse model, complementing any specific data already reported in the literature about this model since its production. It is also particularly relevant for the heterozygous mouse, which mirrors the genotype of the human pathology however requires an extended time to manifest symptoms and to be carefully studied. Copyright 2019 The Authors. Published by Elsevier Inc. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_484,

title = {Long term breeding of the Lmna G609G progeric mouse: Characterization of homozygous and heterozygous models.},

author = {Zaghini A and Sarli G and Barboni C and Sanapo M and Pellegrino V and Diana A and Linta N and Rambaldi J and D'Apice MR and Murdocca M and Baleani M and Baruffaldi F and Fognani R and Mecca R and Festa A and Papparella S and Paciello O and Prisco F and Capanni C and Loi M and Schena E and Lattanzi G and Squarzoni S},

url = {https://www.sciencedirect.com/science/article/pii/S0531556519304127?via%3Dihub},

doi = {10.1016/j.exger.2019.110784},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Experimental gerontology},

volume = {130},

pages = {110784},

abstract = {The transgenic LmnaG609G progeric mouse represents an outstanding animal model for studying the human Hutchinson-Gilford Progeria Syndrome (HGPS) caused by a mutation in the LMNA gene, coding for the nuclear envelope protein Lamin A/C, and, as an important, more general scope, for studying the complex process governing physiological aging in humans. Here we give a comprehensive description of the peculiarities related to the breeding of LmnaG609G mice over a prolonged period of time, and of many features observed in a large colony for a 2-years period. We describe the breeding and housing conditions underlining the possible interference of the genetic background on the phenotype expression. This information represents a useful tool when planning and interpreting studies on the LmnaG609G mouse model, complementing any specific data already reported in the literature about this model since its production. It is also particularly relevant for the heterozygous mouse, which mirrors the genotype of the human pathology however requires an extended time to manifest symptoms and to be carefully studied. Copyright 2019 The Authors. Published by Elsevier Inc. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_147,

title = {Network assessment of demethylation treatment in melanoma: Differential transcriptome-methylome and antigen profile signatures.},

author = {Jiang Z and Cinti C and Taranta M and Mattioli E and Schena E and Singh S and Khurana R and Lattanzi G and Tsinoremas NF and Capobianco E},

url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206686},

doi = {10.1371/journal.pone.0206686},

year  = {2020},

date = {2020-05-14},

journal = {Plos One},

volume = {13},

number = {11},

pages = {e0206686},

abstract = {BACKGROUND: In melanoma, like in other cancers, both genetic alterations and epigenetic underlie the metastatic process. These effects are usually measured by changes in both methylome and transcriptome profiles, whose cross-correlation remains uncertain. We aimed to assess at systems scale the significance of epigenetic treatment in melanoma cells with different metastatic potential. METHODS AND FINDINGS: Treatment by DAC demethylation with 5-Aza-2'-deoxycytidine of two melanoma cell lines endowed with different metastatic potential, SKMEL-2 and HS294T, was performed and high-throughput coupled RNA-Seq and RRBS-Seq experiments delivered differential profiles (DiP) of both transcriptomes and methylomes. Methylation levels measured at both TSS and gene body were studied to inspect correlated patterns with wide-spectrum transcript abundance levels quantified in both protein coding and non-coding RNA (ncRNA) regions. The DiP were then mapped onto standard bio-annotation sources (pathways, biological processes) and network configurations were obtained. The prioritized associations for target identification purposes were expected to elucidate the reprogramming dynamics induced by the epigenetic therapy. The interactomic connectivity maps of each cell line were formed to support the analysis of epigenetically re-activated genes. i.e. those supposedly silenced by melanoma. In particular, modular protein interaction networks (PIN) were used, evidencing a limited number of shared annotations, with an example being MAPK13 (cascade of cellular responses evoked by extracellular stimuli). This gene is also a target associated to the PANDAR ncRNA, therapeutically relevant because of its aberrant expression observed in various cancers. Overall, the non-metastatic SKMEL-2 map reveals post-treatment re-activation of a richer pathway landscape, involving cadherins and integrins as signatures of cell adhesion and proliferation. Relatively more lncRNAs were also annotated, indicating more complex regulation patterns in view of target identification. Finally, the antigen maps matched to DiP display other differential signatures with respect to the metastatic potential of the cell lines. In particular, as demethylated melanomas show connected targets that grow with the increased metastatic potential, also the potential target actionability seems to depend to some degree on the metastatic state. However, caution is required when assessing the direct influence of re-activated genes over the identified targets. In light of the stronger treatment effects observed in non-metastatic conditions, some limitations likely refer to in silico data integration tools and resources available for the analysis of tumor antigens. CONCLUSION: Demethylation treatment strongly affects early melanoma progression by re-activating many genes. This evidence suggests that the efficacy of this type of therapeutic intervention is potentially high at the pre-metastatic stages. The biomarkers that can be assessed through antigens seem informative depending on the metastatic conditions, and networks help to elucidate the assessment of possible targets actionability.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_475,

title = {PCAF Involvement in Lamin A/C-HDAC2 Interplay during the Early Phase of Muscle Differentiation},

author = {Santi S and Cenni V and Capanni C and Lattanzi G and Mattioli E},

url = {https://www.mdpi.com/2073-4409/9/7/1735},

doi = {10.3390/cells9071735},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Cells},

volume = {9},

number = {7},

pages = {E1735},

abstract = {Lamin A/C has been implicated in the epigenetic regulation of muscle gene expression through dynamic interaction with chromatin domains and epigenetic enzymes. We previously showed that lamin A/C interacts with histone deacetylase 2 (HDAC2). In this study, we deepened the relevance and regulation of lamin A/C-HDAC2 interaction in human muscle cells. We present evidence that HDAC2 binding to lamina A/C is related to HDAC2 acetylation on lysine 75 and expression of p300-CBP associated factor (PCAF), an acetyltransferase known to acetylate HDAC2. Our findings show that lamin A and farnesylated prelamin A promote PCAF recruitment to the nuclear lamina and lamin A/C binding in human myoblasts committed to myogenic differentiation, while protein interaction is decreased in differentiating myotubes. Interestingly, PCAF translocation to the nuclear envelope, as well as lamin A/C-PCAF interaction, are reduced by transient expression of lamin A mutated forms causing Emery Dreifuss muscular dystrophy. Consistent with this observation, lamin A/C interaction with both PCAF and HDAC2 is significantly reduced in Emery-Dreifuss muscular dystrophy myoblasts. Overall, these results support the view that, by recruiting PCAF and HDAC2 in a molecular platform, lamin A/C might contribute to regulate their epigenetic activity required in the early phase of muscle differentiation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_434,

title = {Silencing of Euchromatic Transposable Elements as a Consequence of Nuclear Lamina Dysfunction.},

author = {Cavaliere V and Lattanzi G and Andrenacci D},

url = {https://www.mdpi.com/2073-4409/9/3/625},

doi = {10.3390/cells9030625},

year  = {2020},

date = {2020-01-01},

journal = {Cells},

volume = {9},

number = {3},

pages = {e625},

abstract = {Transposable elements (TEs) are mobile genomic sequences that are normally repressed to avoid proliferation and genome instability. Gene silencing mechanisms repress TEs by RNA degradation or heterochromatin formation. Heterochromatin maintenance is therefore important to keep TEs silent. Loss of heterochromatic domains has been linked to lamin mutations, which have also been associated with derepression of TEs. In fact, lamins are structural components of the nuclear lamina (NL), which is considered a pivotal structure in the maintenance of heterochromatin domains at the nuclear periphery in a silent state. Here, we show that a lethal phenotype associated with Lamin loss-of-function mutations is influenced by Drosophila gypsy retrotransposons located in euchromatic regions, suggesting that NL dysfunction has also effects on active TEs located in euchromatic loci. In fact, expression analysis of different long terminal repeat (LTR) retrotransposons and of one non-LTR retrotransposon located near active genes shows that Lamin inactivation determines the silencing of euchromatic TEs. Furthermore, we show that the silencing effect on euchromatic TEs spreads to the neighboring genomic regions, with a repressive effect on nearby genes. We propose that NL dysfunction may have opposed regulatory effects on TEs that depend on their localization in active or repressed regions of the genome.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%u,

title = {Advances in understanding the mechanisms of evasive and innate resistance to mTOR inhibition in cancer cells.},

author = {Chiarini F and Evangelisti C and Lattanzi G and McCubrey JA and Martelli AM},

url = {https://www.sciencedirect.com/science/article/pii/S0167488919300424?via%3Dihub},

doi = {10.1016/j.bbamcr.2019.03.013},

year  = {2019},

date = {2019-02-20},

journal = {Biochimica et biophysica acta. Molecular cell research},

volume = {1866},

number = {8},

pages = {1322-1337},

abstract = {The development of drug-resistance by neoplastic cells is recognized as a major cause of targeted therapy failure and disease progression. The mechanistic (previously mammalian) target of rapamycin (mTOR) is a highly conserved Ser/Thr kinase that acts as the catalytic subunit of two structurally and functionally distinct large multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. Both mTORC1 and mTORC2 play key roles in a variety of healthy cell types/tissues by regulating physiological anabolic and catabolic processes in response to external cues. However, a body of evidence identified aberrant activation of mTOR signaling as a common event in many human tumors. Therefore, mTOR is an attractive target for therapeutic targeting in cancer and this fact has driven the development of numerous mTOR inhibitors, several of which have progressed to clinical trials. Nevertheless, mTOR inhibitors have met with a very limited success as anticancer therapeutics. Among other reasons, this failure was initially ascribed to the activation of several compensatory signaling pathways that dampen the efficacy of mTOR inhibitors. The discovery of these regulatory feedback mechanisms greatly contributed to a better understanding of cancer cell resistance to mTOR targeting agents. However, over the last few years, other mechanisms of resistance have emerged, including epigenetic alterations, compensatory metabolism rewiring and the occurrence of mTOR mutations. In this article, we provide the reader with an updated overview of the mechanisms that could explain resistance of cancer cells to the various classes of mTOR inhibitors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%_48,

title = {Altered adipocyte differentiation and unbalanced autophagy in type 2 Familial Partial Lipodystrophy: an in vitro and in vivo study of adipose tissue browning.},

author = {Pellegrini C and Columbaro M and Schena E and Prencipe S and Andrenacci D and Iozzo P and Angela Guzzardi M and Capanni C and Mattioli E and Loi M and Araujo-Vilar D and Squarzoni S and Cinti S and Morselli P and Giorgetti A and Zanotti L and Gambineri A and Lattanzi G},

url = {https://www.nature.com/articles/s12276-019-0289-0},

doi = {10.1038/s12276-019-0289-0},

year  = {2019},

date = {2019-03-04},

urldate = {2019-03-04},

journal = {Experimental & molecular medicine.},

volume = {51},

number = {8},

pages = {89},

abstract = {Type-2 Familial Partial Lipodystrophy is caused by LMNA mutations. Patients gradually lose subcutaneous fat from the limbs, while they accumulate adipose tissue in the face and neck. Several studies have demonstrated that autophagy is involved in the regulation of adipocyte differentiation and the maintenance of the balance between white and brown adipose tissue. We identified deregulation of autophagy in laminopathic preadipocytes before induction of differentiation. Moreover, in differentiating white adipocyte precursors, we observed impairment of large lipid droplet formation, altered regulation of adipose tissue genes, and expression of the brown adipose tissue marker UCP1. Conversely, in lipodystrophic brown adipocyte precursors induced to differentiate, we noticed activation of autophagy, formation of enlarged lipid droplets typical of white adipocytes, and dysregulation of brown adipose tissue genes. In agreement with these in vitro results indicating conversion of FPLD2 brown preadipocytes toward the white lineage, adipose tissue from FPLD2 patient neck, an area of brown adipogenesis, showed a white phenotype reminiscent of its brown origin. Moreover, in vivo morpho-functional evaluation of fat depots in the neck area of three FPLD2 patients by PET/CT analysis with cold stimulation showed the absence of brown adipose tissue activity. These findings highlight a new pathogenetic mechanism leading to improper fat distribution in lamin A-linked lipodystrophies and show that both impaired white adipocyte turnover and failure of adipose tissue browning contribute to disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%s,

title = {Ankrd2 in Mechanotransduction and Oxidative Stress Response in Skeletal Muscle: New Cues for the Pathogenesis of Muscular Laminopathies.},

author = {Cenni V and Kojic S and Capanni C and Faulkner G and Lattanzi G},

url = {https://www.hindawi.com/journals/omcl/2019/7318796/},

doi = {10.1155/2019/7318796},

year  = {2019},

date = {2019-03-04},

urldate = {2019-03-04},

journal = {Oxidative medicine and cellular longevity},

volume = {2019},

pages = {7318796},

abstract = {Ankrd2 (ankyrin repeats containing domain 2) or Arpp (ankyrin repeat, PEST sequence, and proline-rich region) is a member of the muscle ankyrin repeat protein family. Ankrd2 is mostly expressed in skeletal muscle, where it plays an intriguing role in the transcriptional response to stress induced by mechanical stimulation as well as by cellular reactive oxygen species. Our studies in myoblasts from Emery-Dreifuss muscular dystrophy 2, a LMNA-linked disease affecting skeletal and cardiac muscles, demonstrated that Ankrd2 is a lamin A-binding protein and that mutated lamins found in Emery-Dreifuss muscular dystrophy change the dynamics of Ankrd2 nuclear import, thus affecting oxidative stress response. In this review, besides describing the latest advances related to Ankrd2 studies, including novel discoveries on Ankrd2 isoform-specific functions, we report the main findings on the relationship of Ankrd2 with A-type lamins and discuss known and potential mechanisms involving defective Ankrd2-lamin A interplay in the pathogenesis of muscular laminopathies.},

note = {Review},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%_31,

title = {Differences in cardiac phenotype and natural history of laminopathies with and without neuromuscular onset.},

author = {Ditaranto R and Boriani G and Biffi M and Lorenzini M and Graziosi M and Ziacchi M and Pasquale F and Vitale G and Berardini A and Rinaldi R and Lattanzi G and Potena L and Martin Suarez S and Bacchi Reggiani ML and Rapezzi C and Biagini E},

url = {https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1245-8},

doi = {10.1186/s13023-019-1245-8},

year  = {2019},

date = {2019-02-15},

journal = {Orphanet journal of rare diseases},

volume = {14},

number = {1},

pages = {263},

abstract = {OBJECTIVE: To investigate differences in cardiac manifestations of patients affected by laminopathy, according to the presence or absence of neuromuscular involvement at presentation. METHODS: We prospectively analyzed 40 consecutive patients with a diagnosis of laminopathy followed at a single centre between 1998 and 2017. Additionally, reports of clinical evaluations and tests prior to referral at our centre were retrospectively evaluated. RESULTS: Clinical onset was cardiac in 26 cases and neuromuscular in 14. Patients with neuromuscular presentation experienced first symptoms earlier in life (11 vs 39 years; p <  0.0001) and developed atrial fibrillation/flutter (AF) and required pacemaker implantation at a younger age (28 vs 41 years [p = 0.013] and 30 vs 44 years [p = 0.086] respectively), despite a similar overall prevalence of AF (57% vs 65%; p = 0.735) and atrio-ventricular (A-V) block (50% vs 65%; p = 0.500). Those with a neuromuscular presentation developed a cardiomyopathy less frequently (43% vs 73%; p = 0.089) and had a lower rate of sustained ventricular tachyarrhythmias (7% vs 23%; p = 0.387). In patients with neuromuscular onset rhythm disturbances occurred usually before evidence of cardiomyopathy. Despite these differences, the need for heart transplantation and median age at intervention were similar in the two groups (29% vs 23% [p = 0.717] and 43 vs 46 years [p = 0.593] respectively). CONCLUSIONS: In patients with laminopathy, the type of disease onset was a marker for a different natural history. Specifically, patients with neuromuscular presentation had an earlier cardiac involvement, characterized by a linear and progressive evolution from rhythm disorders (AF and/or A-V block) to cardiomyopathy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%,

title = {Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson-Gilford Progeria Syndrome.},

author = {Aguado J and Sola-Carvajal A and Cancila V and Revêchon G and Ong PF and Jones-Weinert CW and Wallén Arzt E and Lattanzi G and Dreesen O and Tripodo C and Rossiello F and Eriksson M and {d'Adda di Fagagna F}},

url = {https://www.nature.com/articles/s41467-019-13018-3},

doi = {10.1038/s41467-019-13018-3},

year  = {2019},

date = {2019-11-14},

journal = {Nature Communications},

volume = {10},

number = {1},

pages = {4990},

abstract = {Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres. Here we show that progerin-induced telomere dysfunction induces the transcription of tncRNAs. Their functional inhibition by sequence-specific telomeric antisense oligonucleotides (tASOs) prevents full DDR activation and premature cellular senescence in various HGPS cell systems, including HGPS patient fibroblasts. We also show in vivo that tASO treatment significantly enhances skin homeostasis and lifespan in a transgenic HGPS mouse model. In summary, our results demonstrate an important role for telomeric DDR activation in HGPS progeroid detrimental phenotypes in vitro and in vivo.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_159,

title = {Altered modulation of lamin A/C-HDAC2 interaction and p21 expression during oxidative stress response in HGPS.},

author = {Mattioli E and Andrenacci D and Garofalo C and Prencipe S and Scotlandi K and Remondini D and Gentilini D and {Di Blasio AM} and Valente S and Scarano E and Cicchilitti L and Piaggio G and Mai A and Lattanzi G},

url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/acel.12824},

doi = {10.1111/acel.12824},

year  = {2018},

date = {2018-02-14},

journal = {Aging cell},

volume = {17},

number = {5},

pages = {e1282},

abstract = {Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson-Gilford progeria, a severe LMNA-linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C-HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C-HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_182,

title = {BK channel overexpression on plasma membrane of fibroblasts from Hutchinson-Gilford progeria syndrome.},

author = {Zironi I and Gavoci E and Lattanzi G and Virelli A and Amorini F and Remondini D and Castellani G},

url = {https://www.aging-us.com/article/101621/text},

doi = {10.18632/aging.101621},

year  = {2018},

date = {2018-02-15},

journal = {Aging (Albany, NY)},

volume = {10},

number = {11},

pages = {3148-3160},

abstract = {Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder wherein symptoms resembling aspects of aging are manifested at a very early age. It is a genetic condition that occurs due to a de novo mutation in the LMNA gene encoding for the nuclear structural protein lamin A. The lamin family of proteins are thought to be involved in nuclear stability, chromatin structure and gene expression and this leads to heavy effects on the regulation and functionality of the cell machinery. The functional role of the large-conductance calcium-activated potassium channels (BKCa) is still unclear, but has been recently described a strong relationship with their membrane expression, progerin nuclear levels and the ageing process. In this study, we found that: i) the outward potassium membrane current amplitude and the fluorescence intensity of the BKCa channel probe showed higher values in human dermal fibroblast obtained from patients affected by HGPS if compared to that from healthy young subjects; ii) this result appears to correlate with a basic cellular activity such as the replicative boost. We suggest that studying the HGPS also from the electrophysiological point of view might reveal new clues about the normal process of aging.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_118,

title = {Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes. },

author = {Boriani G and Biagini E and Ziacchi M and Malavasi VL and Vitolo M and Talarico M and Mauro E and Gorlato G and Lattanzi G},

url = {https://www.tandfonline.com/doi/full/10.1080/19491034.2018.1506680},

doi = {10.1080/19491034.2018.1506680},

year  = {2018},

date = {2018-02-16},

journal = {Nucleus},

volume = {9},

number = {1},

pages = {442-459},

abstract = {Lamin A/C gene mutations can be associated with cardiac diseases, usually referred to as "cardiolaminopathies" characterized by arrhythmic disorders and/or left ventricular or biventricular dysfunction up to an overt picture of heart failure. The phenotypic cardiac manifestations of laminopathies are frequently mixed in complex clinical patterns and specifically may include bradyarrhythmias (sinus node disease or atrioventricular blocks), atrial arrhythmias (atrial fibrillation, atrial flutter, atrial standstill), ventricular tachyarrhythmias and heart failure of variable degrees of severity. Family history, physical examination, laboratory findings (specifically serum creatine phosphokinase values) and ECG findings are often important "red flags" in diagnosing a "cardiolaminopathy". Sudden arrhythmic death, thromboembolic events or stroke and severe heart failure requiring heart transplantation are the most dramatic complications of the evolution of cardiolaminopathies and appropriate risk stratification is clinically needed combined with clinical follow-up. Treatment with cardiac electrical implantable devices is indicated in case of bradyarrhythmias (implant of a device with pacemaker functions), risk of life-threatening ventricular tachyarrhythmias (implant of an ICD) or in case of heart failure with wide QRS interval (implant of a device for cardiac resynchronization). New technologies introduced in the last 5 years can help physicians to reduce device-related complications, thanks to the extension of device longevity and availability of leadless pacemakers or defibrillators, to be implanted in appropriately selected patients. An improved knowledge of the complex pathophysiological pathways involved in cardiolaminopathies and in the determinants of their progression to more severe forms will help to improve clinical management and to better target pharmacological and non-pharmacological treatments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_111,

title = {Elevated TGF beta2 serum levels in Emery-Dreifuss muscular dystrophy: implications for myocyte and tenocyte differentiation and fibrogenic processes.},

author = {Bernasconi P and Carboni N and Ricci G and Siciliano G and Politano L and Maggi L and Mongini T and Vercelli L and Rodolico C and Biagini E and Boriani G and Ruggiero L and Santoro L and Schena E and Prencipe S and Evangelisti C and Pegoraro E and Morandi L and Columbaro M and Lanzuolo C and Sabatelli P and Cavalcante P and Cappelletti C and Bonne G and Muchir A and Lattanzi G},

url = {https://www.tandfonline.com/doi/abs/10.1080/19491034.2018.1467722},

doi = {10.1080/19491034.2018.1467722},

year  = {2018},

date = {2018-02-13},

journal = {Nucleus},

volume = {25},

number = {1},

pages = {24},

abstract = {Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF beta2) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients. Levels of TGF beta2 are also increased in fibroblast and myoblast cultures established from patient biopsies as well as in serum from mice bearing the H222P Lmna mutation causing Emery-Dreifuss muscular dystrophy in humans. Both patient serum and fibroblast conditioned media activated a TGF beta2-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF beta2 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF beta2-dependent mechanisms were also determined in laminopathic cells, where TGF beta2 activated AKT/mTOR phosphorylation. These data show that TGF beta2 contributes to the pathogenesis of Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B and can be considered a potential biomarker of those diseases. Further, the evidence of TGF beta2 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_150,

title = {Laminopathies.},

author = {Lattanzi G and Maggi L and Araujo-Vilar D},

url = {https://www.tandfonline.com/doi/full/10.1080/19491034.2018.1515606},

doi = {10.1080/19491034.2018.1515606},

year  = {2018},

date = {2018-03-24},

journal = {Nucleus},

volume = {9},

number = {1},

pages = {543-544},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_141,

title = {Lamins and bone disorders: current understanding and perspectives.},

author = {Gargiuli C and Schena E and Mattioli E and Columbaro M and D'Apice MR and Novelli G and Greggi T and Lattanzi G},

url = {http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=25071&pubmed-linkout=1},

doi = {10.18632/oncotarget.25071},

year  = {2018},

date = {2018-04-27},

journal = {Oncotarget},

volume = {9},

number = {32},

pages = {22817-22831},

abstract = {Lamin A/C is a major constituent of the nuclear lamina implicated in a number of genetic diseases, collectively known as laminopathies. The most severe forms of laminopathies feature, among other symptoms, congenital scoliosis, osteoporosis, osteolysis or delayed cranial ossification. Importantly, specific bone districts are typically affected in laminopathies. Spine is severely affected in LMNA-linked congenital muscular dystrophy. Mandible, terminal phalanges and clavicles undergo osteolytic processes in progeroid laminopathies and Restrictive Dermopathy, a lethal developmental laminopathy. This specificity suggests that lamin A/C regulates fine mechanisms of bone turnover, as supported by data showing that lamin A/C mutations activate non-canonical pathways of osteoclastogenesis, as the one dependent on TGF beta 2. Here, we review current knowledge on laminopathies affecting bone and LMNA involvement in bone turnover and highlight lamin-dependent mechanisms causing bone disorders. This knowledge can be exploited to identify new therapeutic approaches not only for laminopathies, but also for other rare diseases featuring bone abnormalities.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_123,

title = {Mandibuloacral dysplasia: A premature ageing disease with aspects of physiological ageing.},

author = {Cenni V and D'Apice MR and Garagnani P and Columbaro M and Novelli G and Franceschi C and Lattanzi G},

url = {https://www.sciencedirect.com/science/article/pii/S1568163717301757?via%3Dihub},

doi = {https://www.sciencedirect.com/science/article/pii/S1568163717301757?via%3Dihub},

year  = {2018},

date = {2018-03-22},

journal = {Ageing research reviews},

volume = {42},

pages = {1-13},

abstract = {Mandibuloacral dysplasia (MAD) is a rare genetic condition characterized by bone abnormalities including localized osteolysis and generalized osteoporosis, skin pigmentation, lipodystrophic signs and mildly accelerated ageing. The molecular defects associated with MAD are mutations in LMNA or ZMPSTE24 (FACE1) gene, causing type A or type B MAD, respectively. Downstream of LMNA or ZMPSTE24 mutations, the lamin A precursor, prelamin A, is accumulated in cells and affects chromatin dynamics and stress response. A new form of mandibuloacral dysplasia has been recently associated with mutations in POLD1 gene, encoding DNA polymerase delta, a major player in DNA replication. Of note, involvement of prelamin A in chromatin dynamics and recruitment of DNA repair factors has been also determined under physiological conditions, at the border between stress response and cellular senescence. Here, we review current knowledge on MAD clinical and pathogenetic aspects and highlight aspects typical of physiological ageing.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_193,

title = {Mandibuloacral dysplasia: A premature ageing disease with aspects of physiological ageing.},

author = {Cenni V and D'Apice MR and Garagnani P and Columbaro M and Novelli G and Franceschi C and Lattanzi G},

url = {http://www.sciencedirect.com/science/article/pii/S1568163717301757?via%3Dihub},

doi = {10.1016/j.arr.2017.12.001},

year  = {2018},

date = {2018-03-22},

journal = {Ageing research reviews},

volume = {42},

pages = {1-13},

abstract = {Mandibuloacral dysplasia (MAD) is a rare genetic condition characterized by bone abnormalities including localized osteolysis and generalized osteoporosis, skin pigmentation, lipodystrophic signs and mildly accelerated ageing. The molecular defects associated with MAD are mutations in LMNA or ZMPSTE24 (FACE1) gene, causing type A or type B MAD, respectively. Downstream of LMNA or ZMPSTE24 mutations, the lamin A precursor, prelamin A, is accumulated in cells and affects chromatin dynamics and stress response. A new form of mandibuloacral dysplasia has been recently associated with mutations in POLD1 gene, encoding DNA polymerase delta, a major player in DNA replication. Of note, involvement of prelamin A in chromatin dynamics and recruitment of DNA repair factors has been also determined under physiological conditions, at the border between stress response and cellular senescence. Here, we review current knowledge on MAD clinical and pathogenetic aspects and highlight aspects typical of physiological ageing.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_146,

title = {Network assessment of demethylation treatment in melanoma: Differential transcriptome-methylome and antigen profile signatures.},

author = {Jiang Z and Cinti C and Taranta M and Mattioli E and Schena E and Singh S and Khurana R and Lattanzi G and Tsinoremas NF and Capobianco E},

url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206686},

doi = {10.1371/journal.pone.0206686},

year  = {2018},

date = {2018-02-21},

journal = { PLoS One},

volume = {13},

issue = {11},

pages = {e0206686},

abstract = {Background: In melanoma, like in other cancers, both genetic alterations and epigenetic underlie the metastatic process. These effects are usually measured by changes in both methylome and transcriptome profiles, whose cross-correlation remains uncertain. We aimed to assess at systems scale the significance of epigenetic treatment in melanoma cells with different metastatic potential. Methods and findings: Treatment by DAC demethylation with 5-Aza-2'-deoxycytidine of two melanoma cell lines endowed with different metastatic potential, SKMEL-2 and HS294T, was performed and high-throughput coupled RNA-Seq and RRBS-Seq experiments delivered differential profiles (DiP) of both transcriptomes and methylomes. Methylation levels measured at both TSS and gene body were studied to inspect correlated patterns with wide-spectrum transcript abundance levels quantified in both protein coding and non-coding RNA (ncRNA) regions. The DiP were then mapped onto standard bio-annotation sources (pathways, biological processes) and network configurations were obtained. The prioritized associations for target identification purposes were expected to elucidate the reprogramming dynamics induced by the epigenetic therapy. The interactomic connectivity maps of each cell line were formed to support the analysis of epigenetically re-activated genes. i.e. those supposedly silenced by melanoma. In particular, modular protein interaction networks (PIN) were used, evidencing a limited number of shared annotations, with an example being MAPK13 (cascade of cellular responses evoked by extracellular stimuli). This gene is also a target associated to the PANDAR ncRNA, therapeutically relevant because of its aberrant expression observed in various cancers. Overall, the non-metastatic SKMEL-2 map reveals post-treatment re-activation of a richer pathway landscape, involving cadherins and integrins as signatures of cell adhesion and proliferation. Relatively more lncRNAs were also annotated, indicating more complex regulation patterns in view of target identification. Finally, the antigen maps matched to DiP display other differential signatures with respect to the metastatic potential of the cell lines. In particular, as demethylated melanomas show connected targets that grow with the increased metastatic potential, also the potential target actionability seems to depend to some degree on the metastatic state. However, caution is required when assessing the direct influence of re-activated genes over the identified targets. In light of the stronger treatment effects observed in non-metastatic conditions, some limitations likely refer to in silico data integration tools and resources available for the analysis of tumor antigens. Conclusion: Demethylation treatment strongly affects early melanoma progression by re-activating many genes. This evidence suggests that the efficacy of this type of therapeutic intervention is potentially high at the pre-metastatic stages. The biomarkers that can be assessed through antigens seem informative depending on the metastatic conditions, and networks help to elucidate the assessment of possible targets actionability.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_388,

title = {Novel histone deacetylase inhibitors induce growth arrest, apoptosis, and differentiation in sarcoma cancer stem cells.},

author = {{Di Pompo G} and Salerno M and Rotili D and Valente S and Zwergel C and Avnet S and Lattanzi G and Baldini N and Mai A},

url = {https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b00126},

doi = {10.1021/acs.jmedchem.5b00126},

year  = {2018},

date = {2018-03-30},

journal = {Journal of Medicinal Chemistry},

volume = {58},

number = {9},

pages = {4073-4079},

abstract = {Musculoskeletal sarcomas are aggressive malignancies of bone and soft tissues often affecting children and adolescents. Histone deacetylase inhibitors (HDACi) have been proposed to counteract cancer stem cells (CSCs) in solid neoplasms. When tested in human osteosarcoma, rhabdomyosarcoma, and Ewing's sarcoma stem cells, the new HDACi MC1742 (1) and MC2625 (2) increased acetyl-H3 and acetyl-tubulin levels and inhibited CSC growth by apoptosis induction. At nontoxic doses, 1 promoted osteogenic differentiation. Further investigation with 1 will be done in preclinical sarcoma models.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_160,

title = {Samp1 Mislocalization in Emery-Dreifuss Muscular Dystrophy.},

author = {Mattioli E and Columbaro M and Jafferali MH and Schena E and Hallberg E and Lattanzi G},

url = {https://www.mdpi.com/2073-4409/7/10/170},

doi = {10.3390/cells7100170},

year  = {2018},

date = {2018-10-19},

urldate = {2015-10-15},

journal = {Cells},

volume = {7},

number = {10},

pages = {pii: E170},

abstract = {pii: E170},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_202,

title = {Emery-Dreifuss Muscular Dystrophy-Associated Mutant Forms of Lamin A Recruit the Stress Responsive Protein Ankrd2 into the Nucleus, Affecting the Cellular Response to Oxidative Stress.},

author = {Angori S and Capanni C and Faulkner G and Bean C and Boriani G and Lattanzi G and Cenni V},

url = {https://www.karger.com/Article/FullText/477309},

doi = {10.1159/000477309},

year  = {2017},

date = {2017-03-07},

urldate = {2017-03-07},

journal = {Cellular Physiology and Biochemistry},

volume = {42},

pages = {169-184},

abstract = {Ankrd2 is a stress responsive protein mainly expressed in muscle cells. Upon the application of oxidative stress, Ankrd2 translocates into the nucleus where it regulates the activity of genes involved in cellular response to stress. Emery-Dreifuss Muscular Dystrophy 2 (EDMD2) is a muscular disorder caused by mutations of the gene encoding lamin A, LMNA. As well as many phenotypic abnormalities, EDMD2 muscle cells also feature a permanent basal stress state, the underlying molecular mechanisms of which are currently unclear. METHODS: Experiments were performed in EDMD2-lamin A overexpressing cell lines and EDMD2-affected human myotubes. Oxidative stress was produced by H2O2 treatment. Co-immunoprecipitation, cellular subfractionation and immunofluorescence analysis were used to validate the relation between Ankrd2 and forms of lamin A; cellular sensibility to stress was monitored by the analysis of Reactive Oxygen Species (ROS) release and cell viability. RESULTS: Our data demonstrate that oxidative stress induces the formation of a complex between Ankrd2 and lamin A. However, EDMD2-lamin A mutants were able to bind and mislocalize Ankrd2 in the nucleus even under basal conditions. Nonetheless, cells co-expressing Ankrd2 and EDMD2-lamin A mutants were more sensitive to oxidative stress than the Ankrd2-wild type lamin A counterpart. CONCLUSIONS: For the first time, we present evidence that in muscle fibers from patients affected by EDMD2, Ankrd2 has an unusual nuclear localization. By introducing a plausible mechanism ruling this accumulation, our data hint at a novel function of Ankrd2 in the pathogenesis of EDMD2-affected cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_293,

title = {Barrier-to-Autointegration Factor (BAF) involvement in prelamin A-related chromatin organization changes.},

author = {Loi M and Cenni V and Duchi S and Squarzoni S and {Lopez-Otin C} and Foisner R and Lattanzi G and Capanni C},

url = {http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=6697&pubmed-linkout=1},

doi = {10.18632/oncotarget.6697},

year  = {2016},

date = {2016-03-08},

urldate = {2016-03-08},

journal = {Oncotarget},

volume = {7},

number = {13},

pages = {15662-15677},

abstract = {Chromatin disorganization is one of the major alterations linked to prelamin A processing impairment. In this study we demonstrate that BAF is necessary to modulate prelamin A effects on chromatin structure. We show that when prelamin A and BAF cannot properly interact no prelamin A-dependent effects on chromatin occur; similar to what is observed in human Nestor Guillermo Progeria Syndrome cells harboring a BAF mutation, in HEK293 cells expressing a BAF mutant unable to bind prelamin A, or in siRNA mediated BAF-depleted HEK293 cells expressing prelamin A. BAF is necessary to induce histone trimethyl-H3K9 as well as HP1-alpha and LAP2-alpha nuclear relocalization in response to prelamin A accumulation. These findings are enforced by electron microscopy evaluations showing how the prelamin A-BAF interaction governs overall chromatin organization. Finally, we demonstrate that the LAP2-alpha nuclear localization defect observed in HGPS cells involves the progerin-BAF interaction, thus establishing a functional link between BAF and prelamin A pathological forms.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_253,

title = {Detection of mesenchymal stem cells senescence by prelamin A accumulation at the nuclear level.},

author = {Bellotti C and Capanni C and Lattanzi G and Donati D and Lucarelli E and Duchi S},

url = {http://springerplus.springeropen.com/articles/10.1186/s40064-016-3091-7},

doi = {10.1186/s40064-016-3091-7},

year  = {2016},

date = {2016-03-08},

urldate = {2016-03-08},

journal = {Springerplus},

volume = {5},

number = {1},

pages = {1427},

abstract = {Human mesenchymal stem cells (MSC), during in vitro expansion, undergo a progressive loss of proliferative potential that leads to the senescent state, associated with a reduction of their "medicinal" properties. This may hampers their efficacy in the treatment of injured tissues. Quality controls on MSC-based cell therapy products should include an assessment of the senescent state. However, a reliable and specific marker is still missing. From studies on lamin-associated disorders, has emerged the correlation between defective lamin A maturation and cellular senescence. FINDINGS: Primary cultured hMSC lines (n = 3), were analyzed by immunostaining at different life-span stages for the accumulation of prelamin A, along with other markers of cellular senescence. During culture, cells at the last stage of their life span displayed evident signs of senescence consistent with the positivity of SA-β-gal staining. We also observed a significant increase of prelamin A positive cells. Furthermore, we verified that the cells marked by prelamin A were also positive for p21(Waf1) while negative for Ki67. CONCLUSIONS: Overall data support that the detection of prelamin A identifies senescent MSC, providing an easy and reliable tool to be use alone or in combination with known senescence markers to screen MSC before their use in clinical applications.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_274,

title = {Potential therapeutic effects of the mtor inhibitors for preventing ageing and progeria-related disorders.},

author = {Evangelisti C and Cenni V and Lattanzi G},

url = {http://onlinelibrary.wiley.com/doi/10.1111/bcp.12928/abstract;jsessionid=34B2DFDBFC206F2806B33262A44B1552.f03t02},

doi = {10.1111/bcp.12928},

year  = {2016},

date = {2016-11-30},

journal = {British Journal of Clinical Pharmacology (Literature Review)},

volume = {82},

number = {5},

pages = {1229-1244},

abstract = {The mammalian target of rapamycin (mTOR) pathway is an highly conserved signal transduction axis involved in many cellular processes such as cell growth, survival, transcription, translation, apoptosis, metabolism, motility and autophagy. Recently, such signaling pathway has come to the attention of the scientific community due to the unexpected finding that inhibition of mTOR by rapamycin, an antibiotic with immunosuppressant and chemotherapeutic properties, extends life-span in diverse animal models. Moreover, rapamycin has been reported to rescue the cellular phenotype in a progeroid syndrome that recapitulates most of the traits of physiological ageing, the Hutchinson-Gilford Progeria (HGPS). The promising perspectives raised by those results warrant a better understanding of mTOR signaling and of potential applications of mTOR inhibitors to counteract ageing-associated diseases and increase longevity. This review is focused on these issues. This article is protected by copyright. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_330,

title = {All-trans retinoic acid and rapamycin normalize Hutchinson Gilford progeria fibroblast phenotype.},

author = {Pellegrini C and Columbaro M and Capanni C and {D'Apice MR} and Cavallo C and Murdocca M and Lattanzi G and Squarzoni S},

url = {http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=4939&pubmed-linkout=1},

doi = {10.18632/oncotarget.4939},

year  = {2015},

date = {2015-03-02},

urldate = {2015-03-02},

journal = {Oncotarget},

volume = {6},

number = {30},

pages = {29914-29928},

abstract = {Hutchinson Gilford progeria syndrome is a fatal disorder characterized by accelerated aging, bone resorption and atherosclerosis, caused by a LMNA mutation which produces progerin, a mutant lamin A precursor. Progeria cells display progerin and prelamin A nuclear accumulation, altered histone methylation pattern, heterochromatin loss, increased DNA damage and cell cycle alterations. Since the LMNA promoter contains a retinoic acid responsive element, we investigated if all-trans retinoic acid administration could lower progerin levels in cultured fibroblasts. We also evaluated the effect of associating rapamycin, which induces autophagic degradation of progerin and prelamin A. We demonstrate that all-trans retinoic acid acts synergistically with low-dosage rapamycin reducing progerin and prelamin A, via transcriptional downregulation associated with protein degradation, and increasing the lamin A to progerin ratio. These effects rescue cell dynamics and cellular proliferation through recovery of DNA damage response factor PARP1 and chromatin-associated nuclear envelope proteins LAP2α and BAF. The combined all-trans retinoic acid-rapamycin treatment is dramatically efficient, highly reproducible, represents a promising new approach in Hutchinson-Gilford Progeria therapy and deserves investigation in ageing-associated disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_345,

title = {Chromatin dynamics and in vitro biomarkers in laminopathies: an overview},

author = {Lattanzi G},

url = {https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-10-S2-O12},

doi = {10.1186/1750-1172-10-S2-O12},

year  = {2015},

date = {2015-02-11},

journal = {Orphanet journal of rare diseases},

volume = {10},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_381,

title = {Modulation of TGFbeta 2 levels by lamin A in U2-OS osteoblast-like cells: understanding the osteolytic process triggered by altered lamins.},

author = {Evangelisti C and Bernasconi P and Cavalcante P and Cappelletti C and D'Apice MR and Sbraccia P and Novelli G and Prencipe S and Lemma S and Baldini N and Avnet S and Squarzoni S and Martelli AM and Lattanzi G},

url = {http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=3232&pubmed-linkout=1},

year  = {2015},

date = {2015-04-10},

journal = {Oncotarget},

volume = {6},

number = {10},

pages = {7424-7437},

abstract = {Transforming growth factor beta (TGFbeta) plays an essential role in bone homeostasis and deregulation of TGFbeta occurs in bone pathologies. Patients affected by Mandibuloacral Dysplasia (MADA), a progeroid disease linked to LMNA mutations, suffer from an osteolytic process. Our previous work showed that MADA osteoblasts secrete excess amount of TGFbeta 2, which in turn elicits differentiation of human blood precursors into osteoclasts. Here, we sought to determine how altered lamin A affects TGFbeta signaling. Our results show that wild-type lamin A negatively modulates TGFbeta 2 levels in osteoblast-like U2-OS cells, while the R527H mutated prelamin A as well as farnesylated prelamin A do not, ultimately leading to increased secretion of TGFbeta 2. TGFbeta 2 in turn, triggers the Akt/mTOR pathway and upregulates osteoprotegerin and cathepsin K. TGFbeta 2 neutralization rescues Akt/mTOR activation and the downstream transcriptional effects, an effect also obtained by statins or RAD001 treatment. Our results unravel an unexpected role of lamin A in TGFbeta 2 regulation and indicate rapamycin analogs and neutralizing antibodies to TGFbeta 2 as new potential therapeutic tools for MADA.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}