Upon tissue injury, the cues released by the inflammatory component of the regenerative environment instruct somatic stem cells toward repairing the damaged area (Stoick-Cooper et al. 2007
). The elucidation of the molecular events underpinning the interplay between the inflammatory infiltrate and tissue progenitors is crucial to devise new strategies toward implementing regeneration of diseased or injured tissues.
Regeneration of diseased muscles relies on muscle stem cells (Satellite cells - SCs), which are activated in response to cytokines and growth factors (Dhawan and Rando 2005
; Kuang and Rudnicki 2008
). The current lack of knowledge on how external cues coordinate gene expression in these cells precludes their selective manipulation through pharmacological interventions.
The inflammatory infiltrate is a transient, yet essential, component of the SC niche and provides the source of locally released cytokines, such as interleukin 1, interleukin 6 and TNFalpha, which regulate muscle regeneration (Gopinath and Rando 2008
; Kuang et al. 2008
). As an inducible element of the SC niche, the inflammatory infiltrate provides an ideal target for selective interventions aimed at manipulating muscle regeneration (Peterson and Guttridge 2008
). However, as local inflammation regulates multiple events within the regeneration process, global anti-inflammatory interventions have both positive and negative effects on SCs (Mozzetta et al. 2009
). Thus, it is important to elucidate the intracellular signalling by which inflammatory cytokines deliver the information to individual genes in SCs.
p38 mitogen-activated protein kinases alpha, beta, gamma and delta respond to cellular stressors, such as inflammatory cytokines. In SCs, this group of kinases convert inflammatory cues into epigenetic information that controls gene expression (Lluis et al. 2006
; Lassar 2009
). The p38 alpha and beta kinases contribute to the assembly of the myogenic transcriptosome on the chromatin of muscle loci, by promoting MyoD-E47 heterodimerization (Lluis et al. 2005
), the recruitment of SWI/SNF chromatin remodelling complex (Simone et al. 2004
; Serra et al. 2007
) and of Ash2L-containing mixed-lineage leukaemia (MLL) methyltransferase complex (Rampalli et al. 2007
). By contrast, p38 gamma represses MyoD transcriptional activity by direct phosphorylation, via association with the H3-K9 methyltransferase KMT1A (Gillespie et al. 2009
). Thus, the p38 kinases can either activate or repress gene expression in SCs, depending on the engagement of specific p38 isoforms. Furthermore, chromatin-associated p38 kinases can control gene transcription by directly targeting components of the transcription machinery (Pokholok et al. 2006
; Chow and Davis 2006
; de Nadal and Posas 2010
), suggesting that signaling via p38 kinases plays a general role in regulating how chromatin-modifying complexes redistribute across the genome in response to extrinsic signals.
During SC differentiation, a large subset of genes is repressed in concomitance with the activation of muscle gene expression (Guasconi and Puri 2009
). Gene repression in flies and mammals is typically associated with methylation of specific lysine residues within histone tails (H3-K27) by the methyltransferase-containing Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) (Simon and Kingston 2009
). PRC-mediated repression of developmental genes is a general mechanism that ensures the maintenance of the undifferentiated phenotype in embryonic stem cells (ESCs) (Boyer et al. 2006
). De-repression of developmental genes in differentiating ESCs correlates with functional inactivation of the enzymatic activity of PRC2, through a physical and functional interplay with a recently described component of PRC2 - the Jumonji- and ARID-domain-containing protein, JARID2 (Pasini et al. 2010
; Shen et al. 2009
; Peng et al. 2010; Panning 2010
). The repressive activity of PRC2 is counterbalanced by trithorax group (trxG)-associated H3-K4 methyltyransferases (Schuettengruber et al. 2007
). The coordinated activity of PRC2 and trxG generates the simultaneous tri-methylation of H3-K27 (H3K273me
) and H3-K4 (H3-K43me
), which typically defines the “bivalent” profile of developmental genes in ESCs; resolution of such bivalency can result either in productive transcription or permanent repression, depending on the relative levels of H3K273me
(Bernstein et al. 2006
). H3-K4- and H3-K27-specific demethylases contribute to the resolution of bivalency in developmental genes during ESC differentiation (Pasini et al. 2008
While PRC-mediated repression of developmental and differentiation genes in ESCs and adult stem cells, respectively, has been extensively investigated, the contribution of PRC2 in gene repression during terminal differentiation of adult stem cells, such as myogenic progenitors, has been suggested (Blais et al. 2007
), but remains relatively unexplored. In particular, it is currently unknown whether in adult muscle stem cells exposed to regeneration signals, PRC2 is re-distributed to repress genes characteristic of the undifferentiated state. Even more puzzling, the identity of the signalling that directs the PRC2 chromatin re-distribution in response to these signals is still obscure.
In the present work, we have identified and characterized a signal-inducible repression of Pax7 expression by PRC2, via inflammation-activated p38 signalling, in SCs. The inflammation-activated p38/PRC2 signalling to Pax7 controls the size and the regeneration activity of SCs and might be exploited for pharmacological manipulation of muscle regeneration.