37 research outputs found

    Chromatin and epigenetics: current biophysical views

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    Recent advances in high-throughput sequencing experiments and their theoretical descriptions have determined fast dynamics of the "chromatin and epigenetics" field, with new concepts appearing at high rate. This field includes but is not limited to the study of DNA-protein-RNA interactions, chromatin packing properties at different scales, regulation of gene expression and protein trafficking in the cell nucleus, binding site search in the crowded chromatin environment and modulation of physical interactions by covalent chemical modifications of the binding partners. The current special issue does not pretend for the full coverage of the field, but it rather aims to capture its development and provide a snapshot of the most recent concepts and approaches. Eighteen open-access articles comprising this issue provide a delicate balance between current theoretical and experimental biophysical approaches to uncover chromatin structure and understand epigenetic regulation, allowing free flow of new ideas and preliminary results

    Skeletal muscle wasting and renewal: a pivotal role of myokine IL-6

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    Musculoskeletal senescence: a moving target ready to be eliminated

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    Aging is the prime risk factor for the broad-based development of diseases. Frailty is a phenotypical hallmark of aging and is often used to assess whether the predicted benefits of a therapy outweigh the risks for older patients. Senescent cells form as a consequence of unresolved molecular damage and persistently secrete molecules that can impair tissue function. Recent evidence shows senescent cells can chronically interfere with stem cell function and drive aging of the musculoskeletal system. In addition, targeted apoptosis of senescent cells can restore tissue homeostasis in aged animals. Thus, targeting cellular senescence provides new therapeutic opportunities for the intervention of frailty-associated pathologies and could have pleiotropic health benefits.The authors acknowledge support for MB from Dutch Cancer Society Grant UMCU-7141 awarded to PdK, and for EP and PMC from ERC-2016-AdG-741966 (STEM-AGING), SAF2015-67369-R, MDA and AFM. The DCESX/UPF is recipient of a ‘María de Maeztu’ Program for Units of Excellence in R&D MDM-2014-0370 (Government of Spain

    The dystrophin glycoprotein complex regulates the epigenetic activation of muscle stem cell commitment

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    Asymmetrically dividing muscle stem cells in skeletal muscle give rise to committed cells, where the myogenic determination factor Myf5 is transcriptionally activated by Pax7. This activation is dependent on Carm1, which methylates Pax7 on multiple arginine residues, to recruit the ASH2L:MLL1/2:WDR5:RBBP5 histone methyltransferase complex to the proximal promoter of Myf5. Here, we found that Carm1 is a specific substrate of p38Îł/MAPK12 and that phosphorylation of Carm1 prevents its nuclear translocation. Basal localization of the p38Îł/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through ÎČ1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38Îł/ÎČ1-syntrophin interactions are abrogated, resulting in enhanced Carm1 phosphorylation. The resulting progenitors exhibit reduced Carm1 binding to Pax7, reduced H3K4-methylation of chromatin, and reduced transcription of Myf5 and other Pax7 target genes. Therefore, our experiments suggest that dysregulation of p38Îł/Carm1 results in altered epigenetic gene regulation in Duchenne muscular dystrophy.We thank Drs. Jeffrey Dilworth and Lynn Megeney for careful reading of the manuscript. We also thank Jennifer Ritchie for animal husbandry, Dr. Lawrence Puente for mass spectrometry analysis, Dr. ChloĂ« van Oostende for microscopy and imaging analysis, Paul Oleynik for FACS, and Fan Xiao, Natasha Mercier, and David Wilson for technical assistance. N.C.C. is a recipient of the Centre for Neuromuscular Disease Scholarship in Translational Research Award from the University of Ottawa Brain and Mind Research Institute and was supported by Postdoctoral fellowships from the Canadian Institutes of Health Research (CIHR) and the Ontario Institute for Regenerative Medicine (OIRM). F.P.C. was supported by a Postdoctoral fellowship from the French Muscular Dystrophy Association (AFM)-TĂ©lĂ©thon (380782). C.E.B. is supported by a Postdoctoral fellowship from OIRM. M.L. was supported by a Postdoctoral fellowship from CIHR. P.M.-C. acknowledges support from ERC-2016-AdG-741966 (STEM-AGING) and SAF2015-67369-R. M.A.R. holds the Canada Research Chair in Molecular Genetics. These studies were carried out with support of grants to M.A.R. from the US NIH (R01AR044031), the Canadian Institutes of Health Research (FDN-148387), the Muscular Dystrophy Association (USA), E-Rare-2: Canadian Institutes of Health Research/Muscular Dystrophy Canada (ERA-132935), and the Stem Cell Network

    Autophagy maintains stemness by preventing senescence

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    During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia

    Genetic rescue of mitochondrial and skeletal muscle impairment in an induced pluripotent stem cells model of coenzyme Q10 deficiency

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    et al.Coenzyme Q (CoQ) plays a crucial role in mitochondria as an electron carrier within the mitochondrial respiratory chain (MRC) and is an essential antioxidant. Mutations in genes responsible for CoQ biosynthesis (COQ genes) cause primary CoQ deficiency, a rare and heterogeneous mitochondrial disorder with no clear genotype–phenotype association, mainly affecting tissues with high-energy demand including brain and skeletal muscle (SkM). Here, we report a four-year-old girl diagnosed with minor mental retardation and lethal rhabdomyolysis harboring a heterozygous mutation (c.483G > C (E161D)) in COQ4. The patient's fibroblasts showed a decrease in [CoQ], CoQ biosynthesis, MRC activity affecting complexes I/II + III, and respiration defects. Bona fide induced pluripotent stem cell (iPSCs) lines carrying the COQ4 mutation (CQ4-iPSCs) were generated, characterized and genetically edited using the CRISPR-Cas9 system (CQ4-iPSCs). Extensive differentiation and metabolic assays of control-iPSCs, CQ4-iPSCs and CQ4-iPSCs demonstrated a genotype association, reproducing the disease phenotype. The COQ4 mutation in iPSC was associated with CoQ deficiency, metabolic dysfunction, and respiration defects. iPSC differentiation into SkM was compromised, and the resulting SkM also displayed respiration defects. Remarkably, iPSC differentiation in dopaminergic or motor neurons was unaffected. This study offers an unprecedented iPSC model recapitulating CoQ deficiency-associated functional and metabolic phenotypes caused by COQ4 mutation.This work was supported by the ISCIII/FEDER (E-Rare-2 Call PI12/03112 to P.M.), FIS/ISCIII/FEDER project (PI14/01962 to P.N.) and the European Research Council (ERC-2014-CoG646903 to P.M.). D.R.M. and C.P. are supported by PFIS scholarships (FI11/0511 and FI12/00468, respectively). C.B is supported by a Miguel Servet II contract (CPII13/00011). P.M. also acknowledges the financial support from The Obra Social La Caixa-Fundacio Josep Carreras and The Generalitat de Catalunya (SGR330). P.M. and J.L.-B. are investigators of the Spanish Cell Therapy cooperative network (TERCEL). A.G. is supported by Ramon y Cajal Program (RyC-2013–13221).Peer Reviewe

    3-Deazaadenosine alleviates senescence to promote cellular fitness and cell therapy efficiency in mice

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    Cellular senescence is a stable type of cell cycle arrest triggered by different stresses. As such, senescence drives age-related diseases and curbs cellular replicative potential. Here, we show that 3-deazaadenosine (3DA), an S-adenosyl homocysteinase inhibitor, alleviates replicative and oncogene-induced senescence. 3DA-treated senescent cells showed reduced global histone H3 lysine 36 trimethylation, an epigenetic modification that marks the bodies of actively transcribed genes. By integrating transcriptome and epigenome data, we demonstrate that 3DA treatment affects key factors of the senescence transcriptional program. Notably, 3DA treatment alleviated senescence and increased the proliferative and regenerative potential of muscle stem cells from very old mice in vitro and in vivo. Moreover, ex vivo 3DA treatment was sufficient to enhance the engraftment of human umbilical cord blood cells in immunocompromised mice. Together, our results identify 3DA as a promising drug enhancing the efficiency of cellular therapies by restraining senescence
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