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UTX demethylase activity is required for satellite cell–mediated muscle regeneration
Hervé Faralli, … , Kai Ge, F. Jeffrey Dilworth
Hervé Faralli, … , Kai Ge, F. Jeffrey Dilworth
Published March 21, 2016
Citation Information: J Clin Invest. 2016;126(4):1555-1565. https://doi.org/10.1172/JCI83239.
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Research Article Muscle biology Article has an altmetric score of 8

UTX demethylase activity is required for satellite cell–mediated muscle regeneration

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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

Hervé Faralli, Chaochen Wang, Kiran Nakka, Aissa Benyoucef, Soji Sebastian, Lenan Zhuang, Alphonse Chu, Carmen G. Palii, Chengyu Liu, Brendan Camellato, Marjorie Brand, Kai Ge, F. Jeffrey Dilworth

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Figure 5

UTX demethylase activity is required for H3K27me3 removal on muscle differentiation gene.

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UTX demethylase activity is required for H3K27me3 removal on muscle diff...
Primary myoblasts from female UtxKI/KI or UtxWT/WT mice were isolated, sorted by FACS, and expanded in vitro. Myogenic differentiation was induced for 24 hours. (A and B) RNA-Seq analysis was then performed to identify genes whose expression is modified in differentiating myoblasts from UtxKI/KI mice compared with UtxWT/WT mice. (A) A heatmap is shown for selected genes of different ontologies that are differentially expressed in the UtxKI/KI myoblasts (P < 0.05). (B) GO analysis of the genes downregulated in myoblasts from the UtxKI/KI mice shows highly significant enrichment of genes involved in muscle development and function. (C) ChIP analysis was performed to analyze the enrichment of UTX at the Myog, CKm, and Tnnc2 promoters. (D) Native-ChIP analysis was performed to determine H3K27me3 enrichment at the Myog, CKm, and Tnnc2 promoters. Values are presented as the average enrichment as a percentage of input ± SD. Statistical analysis was performed using an unpaired t test where *P < 0.05, n = 3.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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