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• W2272453669 abstract "Satellite cells comprise a pool of quiescent stem cells that repair muscle damage, but the mechanisms enforcing their quiescence are poorly defined. In this issue of Cell Stem Cell, Boonsanay et al., 2016Boonsanay V. Zhang T. Georgieva A. Kostin S. Qi H. Yuan X. Zhou Y. Braun T. Cell Stem Cell. 2016; 18 (this issue): 229-242PubMed Google Scholar show that the histone methyltransferase Suv4-20H1 maintains satellite cell quiescence by promoting a heterochromatic state through transcriptional repression of the myogenic master regulator MyoD. Satellite cells comprise a pool of quiescent stem cells that repair muscle damage, but the mechanisms enforcing their quiescence are poorly defined. In this issue of Cell Stem Cell, Boonsanay et al., 2016Boonsanay V. Zhang T. Georgieva A. Kostin S. Qi H. Yuan X. Zhou Y. Braun T. Cell Stem Cell. 2016; 18 (this issue): 229-242PubMed Google Scholar show that the histone methyltransferase Suv4-20H1 maintains satellite cell quiescence by promoting a heterochromatic state through transcriptional repression of the myogenic master regulator MyoD. Satellite cells are an adult stem cell population residing in skeletal muscle that endows the tissue with the capacity to regenerate and repair damaged myofibers (Aziz et al., 2012Aziz A. Sebastian S. Dilworth F.J. Stem Cell Rev. 2012; 8: 609-622Crossref PubMed Scopus (37) Google Scholar). In healthy muscle, satellite cells reside in a quiescent state where they ensure that a pool of muscle stem cells is available to repair damaged myofibers throughout our lifetimes (Rai et al., 2014Rai M. Nongthomba U. Grounds M.D. Curr. Top. Dev. Biol. 2014; 108: 247-281Crossref PubMed Scopus (39) Google Scholar). In response to myofiber damage, satellite cells transition from a quiescent to an activated state by turning on expression of the muscle-specific transcription factor MyoD. Most of the activated satellite cells will then rapidly proliferate to generate sufficient muscle progenitor cells to form new myofibers, while a small number of the activated satellite cells will return to quiescence to repopulate the satellite cell niche. Though several studies have identified factors important for the transition between the quiescent and activated satellite cell states (Rodgers et al., 2014Rodgers J.T. King K.Y. Brett J.O. Cromie M.J. Charville G.W. Maguire K.K. Brunson C. Mastey N. Liu L. Tsai C.R. et al.Nature. 2014; 510: 393-396PubMed Google Scholar), we continue to have a poor understanding of the mechanisms that regulate this important cell fate transition. Now in Cell Stem Cell, Boonsanay et al., 2016Boonsanay V. Zhang T. Georgieva A. Kostin S. Qi H. Yuan X. Zhou Y. Braun T. Cell Stem Cell. 2016; 18 (this issue): 229-242PubMed Google Scholar provide exciting new insight into the control of satellite cell quiescence and show that the histone H4 lysine 20 (H4K20) methyltransferase Suv4-20H1 is critically required for maintenance of the condensed heterochromatic state, thereby preventing satellite cell activation (Figure 1). Satellite cells are easily identifiable by immunofluorescence microscopy of muscle cross-sections, where cells expressing the transcription factor Pax7 are positioned in the interstitial space between adjacent myofibers. Satellite cells are also easily discernable by electron microscopy; the relatively small myofiber-associated cells contain very little cytoplasm and a high content of dense heterochromatin within the nucleus (Shi and Garry, 2006Shi X. Garry D.J. Genes Dev. 2006; 20: 1692-1708Crossref PubMed Scopus (386) Google Scholar). Satellite cells can be isolated using a handful of different cell surface markers, but they are usually characterized by the expression of the transcription factor Pax7 that is required to maintain the cell lineage (Günther et al., 2013Günther S. Kim J. Kostin S. Lepper C. Fan C.M. Braun T. Cell Stem Cell. 2013; 13: 590-601Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, Seale et al., 2000Seale P. Sabourin L.A. Girgis-Gabardo A. Mansouri A. Gruss P. Rudnicki M.A. Cell. 2000; 102: 777-786Abstract Full Text Full Text PDF PubMed Scopus (1654) Google Scholar). In contrast to many studies that have used isolated satellite cells to characterize changes in gene expression between the quiescent and activated states, Boonsanay et al. perform an in vivo microscopy-based assessment of changes in satellite cell quiescence. They directly visualize heterochromatic structure decondensation and accumulation of MyoD protein to find that heterochromatin formation in satellite cells is mediated through direct binding of Suv4-20H1 to the MyoD Distal Regulatory Region (DRR) enhancer, where it establishes a transcriptionally repressive H4K20-dimethyl mark to enforce quiescence. Following satellite cell-specific ablation of Suv4-20H1 in mice, electron microscopy showed that satellite cells maintained their natural position within the niche but lost their characteristic enrichment of heterochromatin. This change in chromatin structure was accompanied by activation of MyoD expression and loss of global H3K27me3 levels. The expression of MyoD suggests that Suv4-20H1-depleted satellite cells enter an activated state, though these cells do not commit to expanding the muscle progenitor pool since an increase in the number of Ki67-positive cells was not observed. This finding shows that the expression of MyoD is not sufficient to induce expansion of the satellite cell pool and suggests that activated satellite cells and proliferating myogenic progenitors are independent cellular states. The authors then utilized a cardiotoxin-induced muscle injury model, in which polypeptide-induced lysis of myofibers causes activation of the quiescent satellite cells to mediate regeneration of damaged muscle. They found that satellite cells lacking Suv4-20H1 can efficiently repair damaged myofibers. However, repeated injuries to the same muscle revealed that satellite cell-specific loss of Suv4-20H1 impairs the long-term ability of muscle to regenerate itself, due to a drastic reduction in the number of myofiber-associated satellite cells. This suggests that Suv4-20H1 is required to re-establish a condensed heterochromatic state and maintain satellite cell numbers and that the absence of Suv4-20H1 results in depletion of the satellite cell pool. Importantly, heterochromatin decondensation in Suv4-20H1-depleted satellite cells was shown to be a consequence of precocious MyoD expression. Genetic reduction of MyoD levels in animals with satellite cell-specific loss of Suv4-20H1 re-established normal heterochromatin in satellite cells and restored their ability to support long-term muscle regeneration. These findings strongly support a model in which Suv4-20H1 maintains the quiescent state of satellite cells by ensuring transcriptional repression of MyoD. The profound effect of MyoD expression on global chromatin structure in satellite cells is an interesting finding in light of its role as the “Master Regulator of Myogenesis.” Exogenous expression of MyoD in fibroblasts is sufficient to establish the myogenic gene expression program (Davis et al., 1987Davis R.L. Weintraub H. Lassar A.B. Cell. 1987; 51: 987-1000Abstract Full Text PDF PubMed Scopus (2470) Google Scholar), and ChIP-sequencing analysis has demonstrated that exogenous expression of MyoD in fibroblasts leads to de novo acetylation of histones at target gene loci (Cao et al., 2010Cao Y. Yao Z. Sarkar D. Lawrence M. Sanchez G.J. Parker M.H. MacQuarrie K.L. Davison J. Morgan M.T. Ruzzo W.L. et al.Dev. Cell. 2010; 18: 662-674Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar). With the wide-spread binding of MyoD previously described in primary myoblasts (Cao et al., 2010Cao Y. Yao Z. Sarkar D. Lawrence M. Sanchez G.J. Parker M.H. MacQuarrie K.L. Davison J. Morgan M.T. Ruzzo W.L. et al.Dev. Cell. 2010; 18: 662-674Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar), it is tempting to speculate that activation of MyoD expression leads to global decondensation of heterochromatin in activated satellite cells through acetylation of target loci. Though the authors did not observe marked changes in global H3K9 acetylation levels upon the transition from the quiescent to the activated satellite cell state, these findings do not preclude the possibility that MyoD expression (and binding at target loci) permits acetylation of histones at alternate lysine residues. Moving forward, it will be important to determine whether p300-mediated H3K27 acetylation marks associated with enhancer activation, or other less-studied histone acetylation marks, play a role in MyoD-dependent heterochromatin decondensation upon satellite cell activation. It is also important to point out that similar decondensation of heterochromatin in satellite cells has previously been observed upon ablation of Pax7 (Günther et al., 2013Günther S. Kim J. Kostin S. Lepper C. Fan C.M. Braun T. Cell Stem Cell. 2013; 13: 590-601Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar). These findings suggest antagonism between the myogenic transcription factors Pax7 and MyoD, where Pax7 helps create and maintain the condensed chromatin state characteristic of quiescent satellite cells, while MyoD functions to activate satellite cells through the establishment of an open chromatin state. Since Pax7 continues to be expressed along with MyoD in activated satellite cells, the chromatin decondensation activity of MyoD appears to be dominant over the chromatin condensation activity of Pax7. Mechanistically, we note that ChIP-seq studies did not identify MyoD as a gene that is directly repressed by Pax7 (Soleimani et al., 2012Soleimani V.D. Punch V.G. Kawabe Y. Jones A.E. Palidwor G.A. Porter C.J. Cross J.W. Carvajal J.J. Kockx C.E. van IJcken W.F. et al.Dev. Cell. 2012; 22: 1208-1220Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar), suggesting that Pax7 does not target Suv4-20H1 to the MyoD locus to block expression. Future studies will be required to establish how MyoD and Pax7 act in an antagonizing manner to modulate the chromatin state controlling the transition between the quiescent and activated satellite cell fates. In summary, the elegant work of Boonsanay et al., 2016Boonsanay V. Zhang T. Georgieva A. Kostin S. Qi H. Yuan X. Zhou Y. Braun T. Cell Stem Cell. 2016; 18 (this issue): 229-242PubMed Google Scholar identified a pivotal role of Suv4-20H1 in governing the quiescent state of satellite cells through direct repression of the myogenic master regulator MyoD. These findings provide strong evidence for the concept that satellite cell quiescent state is not a default cellular state but is instead a cellular state that must be actively maintained and re-established throughout one’s lifetime. We thank Drs. Marjorie Brand and Michael Rudnicki (Ottawa Hospital Research Institute) for insightful discussions. Work in the Dilworth laboratory is supported by a Foundation Scheme Grant (FDN 143330) from the Canadian Institutes of Health Research. Y.L. is the recipient of a doctoral scholarship from the Chinese Scholarship Council. Regulation of Skeletal Muscle Stem Cell Quiescence by Suv4-20h1-Dependent Facultative Heterochromatin FormationBoonsanay et al.Cell Stem CellDecember 5, 2015In BriefBoonsanay et al. show that Suv4-20h1 dynamically regulates muscle stem cell quiescence by regulating facultative heterochromatin formation. Disruption of Suv4-20h1 leads to activation of the MyoD locus and persistent stem cell activation, eventually leading to stem cell depletion and loss of skeletal muscle regeneration. Full-Text PDF Open Archive" @default.
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• W2272453669 title "Compacting Chromatin to Ensure Muscle Satellite Cell Quiescence" @default.
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