Regulation of Skeletal Muscle Stem Cell Quiescence by Suv4-20h1-Dependent Facultative Heterochromatin Formation

Abstract

Skeletal muscle stem cells (MuSCs) are required for regeneration of adult muscle following injury, a response that demands activation of mainly quiescent MuSCs. Despite the need for dynamic regulation of MuSC quiescence, relatively little is known about the determinants of this property. Here, we show that Suv4-20h1, an H4K20 dimethyltransferase, controls MuSC quiescence by promoting formation of facultative heterochromatin (fHC). Deletion of Suv4-20h1 reduces fHC and induces transcriptional activation and repositioning of the MyoD locus away from the heterochromatic nuclear periphery. These effects promote MuSC activation, resulting in stem cell depletion and impaired long-term muscle regeneration. Genetic reduction of MyoD expression rescues fHC formation and lost MuSC quiescence, restoring muscle regeneration capacity in Suv4-20h1 mutants. Together, these findings reveal that Suv4-20h1 actively regulates MuSC quiescence via fHC formation and control of the MyoD locus, thereby guarding and preserving the stem cell pool over a lifetime.

Transient translational quiescence in primordial germ cells

“…The paradigmatic quiescent stem cell is the hematopoietic lineage, which is maintained at a low cell cycle, but can be stimulated to form new blood cells in response to signaling (Valcourt et al, 2012;Nakamura-Ishizu et al, 2014). Recent research has documented that many tissues in human have quiescent stem cells (Rezza et al, 2014), including skeletal muscle (Boonsanay et al, 2016;Fukada et al, 2007), the hair follicle (Morris et al, 2004;Goldstein and Horsley, 2012), the intestine (Richmond et al, 2015a,b) and even the central nervous system (Cheung and Rando, 2013;Webb et al, 2013;Gilboa and Lehmann, 2004). Unfortunately, quiescent stem cells are also common in cancer and are the bane of chemotherapy; a quiescent cancer stem cell escapes many of the cancer treatments intending to kill the rapidly proliferating cells (Cheung and Rando, 2013;Nakamura-Ishizu et al, 2014).…”

Survival in Quiescence Requires the Euchromatic Deployment of Clr4/SUV39H by Argonaute-Associated Small RNAs

“…For example, histone hypoacetylation (McKnight et al, 2015; Mews et al, 2014) and redistribution of a constitutive heterochromatic histone mark, histone H4 lysine 20 methylation (H4K20me) (Boonsanay et al, 2016; Evertts et al, 2013), are critical for G0 in yeast and mammalian cells, respectively. Also in quiescent mouse and human cells, the level and distribution of histone H3 lysine 9 methylation (H3K9me), the hallmark of eukaryotic heterochromatin, appears to be different compared to proliferative cells (Grigoryev et al, 2004).…”

Regulation of Muscle Stem Cell Functions: A Focus on the p38 MAPK Signaling Pathway

“…Methylated Pax7 directly binds to the Thritorax complex resulting in its recruitment to the Myf5 promoter, leading to H3K4 methylation, Myf5 expression and myogenic commitment (Kawabe et al, 2012). Finally, a very recent study has shown that the histone methyltransferase Suv4-20H1 is necessary to maintain satellite cell quiescence by causing a condensed state of the heterochromatin through the transcriptional repression of MyoD (Boonsanay et al, 2016). Indeed, Suv4-20H1 binds directly to the MyoD Distal Regulatory Region enhancer and catalyzes the transcriptionally repressive H4K20me2 mark to enforce quiescence.…”