Rodgers, J.T., King, K.Y., Brett, J.O., Cromie, M.J., Charville, G.W., Maguire, K.K., Brunson, C., Mas- tey, N., Liu, L., Tsai, C.R., et al. (2014). Nature 510, 393–396. Schultz, E., Jaryszak, D.L., and Valliere, C.R. (1985). Muscle Nerve. 8, 217–222. Siegel, A.L., Kuhlmann, P.K., and Cornelison, D.D. (2011). Skelet. Muscle 1,7. Webster, M.T., Manor, U., Lippincott-Schwartz, J., and Fan, C.M. (2016). Cell Stem Cell 18, this issue, 243–252. Yin, H., Price, F., and Rudnicki, M.A. (2013). Phys- iol. Rev. 93, 23–67. Zammit, P.S., Golding, J.P., Nagata, Y., Hudon, V., Partridge, T.A., and Beauchamp, J.R. (2004). J. Cell Biol. 166, 347–357. Compacting Chromatin to Ensure Muscle Satellite Cell Quiescence Yuefeng Li 1,2 and F. Jeffrey Dilworth 1,2, * 1 Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada 2 Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada *Correspondence: jdilworth@ohri.ca http://dx.doi.org/10.1016/j.stem.2016.01.009 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. (2016) 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 pop- ulation residing in skeletal muscle that endows the tissue with the capacity to regenerate and repair damaged myofib- ers (Aziz et al., 2012). 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., 2014). 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 sat- ellite cells will return to quiescence to re- populate 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., 2014), 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. (2016) provide exciting new insight into the control of satellite cell quiescence and show that the histone H4 lysine 20 (H4K20) methyltransferase Suv4-20H1 is criti- cally 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 ex- pressing the transcription factor Pax7 are positioned in the interstitial space be- tween adjacent myofibers. Satellite cells are also easily discernable by electron mi- croscopy; the relatively small myofiber- associated cells contain very little cytoplasm and a high content of dense heterochromatin within the nucleus (Shi and Garry, 2006). 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 (Gu ¨ nther et al., 2013; Seale et al., 2000). In contrast to many studies that have used isolated satellite cells to charac- terize changes in gene expression be- tween 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 accumula- tion of MyoD protein to find that hetero- chromatin formation in satellite cells is mediated through direct binding of Suv4-20H1 to the MyoD Distal Regu- latory Region (DRR) enhancer, where it establishes a transcriptionally repres- sive H4K20-dimethyl mark to enforce quiescence. Following satellite cell-specific ablation of Suv4-20H1 in mice, electron micro- scopy showed that satellite cells main- tained their natural position within the niche but lost their characteristic enrich- ment 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 162 Cell Stem Cell 18, February 4, 2016 ª2016 Elsevier Inc. Cell Stem Cell Previews