title: UTX demethylase activity is required for satellite cell-mediated muscle regeneration.
abstract: The X chromosome-encoded histone demethylase UTX (also known as KDM6A) mediates removal of repressive trimethylation of histone H3 lysine 27 (H3K27me3) to establish transcriptionally permissive chromatin. Loss of UTX in female mice is embryonic lethal. Unexpectedly, male UTX-null mice escape embryonic lethality due to expression of UTY, a paralog that lacks H3K27 demethylase activity, suggesting an enzyme-independent role for UTX in development and thereby challenging the need for active H3K27 demethylation in vivo. However, the requirement for active H3K27 demethylation in stem cell-mediated tissue regeneration remains untested. Here, we employed an inducible mouse KO that specifically ablates Utx in satellite cells (SCs) and demonstrated that active H3K27 demethylation is necessary for muscle regeneration. Loss of UTX in SCs blocked myofiber regeneration in both male and female mice. Furthermore, we demonstrated that UTX mediates muscle regeneration through its H3K27 demethylase activity, as loss of demethylase activity either by chemical inhibition or knock-in of demethylase-dead UTX resulted in defective muscle repair. Mechanistically, dissection of the muscle regenerative process revealed that the demethylase activity of UTX is required for expression of the transcription factor myogenin, which in turn drives differentiation of muscle progenitors. Thus, we have identified a critical role for the enzymatic activity of UTX in activating muscle-specific gene expression during myofiber regeneration and have revealed a physiological role for active H3K27 demethylation in vivo.
authors.forename: Hervé
authors.initials: H
authors.lastname: Faralli
authors.forename: Chaochen
authors.initials: C
authors.lastname: Wang
authors.forename: Kiran
authors.initials: K
authors.lastname: Nakka
authors.forename: Aissa
authors.initials: A
authors.lastname: Benyoucef
authors.forename: Soji
authors.initials: S
authors.lastname: Sebastian
authors.forename: Lenan
authors.initials: L
authors.lastname: Zhuang
authors.forename: Alphonse
authors.initials: A
authors.lastname: Chu
authors.forename: Carmen G
authors.initials: CG
authors.lastname: Palii
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.forename: Brendan
authors.initials: B
authors.lastname: Camellato
authors.forename: Marjorie
authors.initials: M
authors.lastname: Brand
authors.forename: Kai
authors.initials: K
authors.lastname: Ge
authors.forename: F Jeffrey
authors.initials: FJ
authors.lastname: Dilworth
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D055879:Gene Knock-In Techniques; D056466:Histone Demethylases / Q000096:biosynthesis* / Q000235:genetics; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009210:Myofibrils / Q000502:physiology*; D018008:Myogenin / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology*; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000201:enzymology*
chemical_list: D006657:Histones; C503801:Myog protein, mouse; D018008:Myogenin; D056466:Histone Demethylases; C111778:Utx protein, mouse