TNF/p38α/polycomb signaling to Pax7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration.
How regeneration cues are converted into the epigenetic information that controls gene expression in adult stem cells is currently unknown. We identified an inflammation-activated signaling in muscle stem (satellite) cells, by which the polycomb repressive complex 2 (PRC2) represses Pax7 expression during muscle regeneration. TNF-activated p38α kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzymatic subunit of the complex, leading to the formation of repressive chromatin on Pax7 promoter. TNF-α antibodies stimulate satellite cell proliferation in regenerating muscles of dystrophic or normal mice. Genetic knockdown or pharmacological inhibition of the enzymatic components of the p38/PRC2 signaling--p38α and EZH2--invariably promote Pax7 expression and expansion of satellite cells that retain their differentiation potential upon signaling resumption. Genetic knockdown of Pax7 impaired satellite cell proliferation in response to p38 inhibition, thereby establishing the biological link between p38/PRC2 signaling to Pax7 and satellite cell decision to proliferate or differentiate.
Palacios
Daniela
D
Dulbecco Telethon Institute (DTI), IRCCS Fondazione Santa Lucia and European Brain Research Institute, 00143 Roma, Italy.
Mozzetta
Chiara
C
Consalvi
Silvia
S
Caretti
Giuseppina
G
Saccone
Valentina
V
Proserpio
Valentina
V
Marquez
Victor E
VE
Valente
Sergio
S
Mai
Antonello
A
Forcales
Sonia V
SV
Sartorelli
Vittorio
V
Puri
Pier Lorenzo
PL
D000818:Animals; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D007249:Inflammation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D051763:PAX7 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic; D052097:Quadriceps Muscle / Q000378:metabolism / Q000502:physiology*; D012038:Regeneration; D012097:Repressor Proteins / Q000378:metabolism*; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases