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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 April 1, 2016; First published March 21, 2016
Citation Information: J Clin Invest. 2016;126(4):1555-1565. https://doi.org/10.1172/JCI83239.
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Categories: Research Article Muscle biology Stem cells

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 1

SC-mediated muscle regeneration is impaired in both male and female UTXmKO mice.

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SC-mediated muscle regeneration is impaired in both male and female UTXm...
(A and B) Cross sections of TA muscles from female (A) or male mice (B) were visualized after H&E staining to evaluate muscle integrity in noninjured (normal muscle) and CTX-injected (regenerating muscle) muscle at 7 days after tissue injury. Necrotic tissues and the infiltrating interstitial cells are indicated by red arrows. Each image panel is visualized under ×20 magnification and represents a total area of 90,000 μm2. A schematic representation of the experimental procedure is shown, with tamoxifen injections indicated by orange arrows and CTX injection by red arrows. Myofiber calibers within the TA muscle of a representative mouse were calculated and plotted for each condition (n > 500 total fibers per condition). Each dot represents the area of a single myofiber; the horizontal bar corresponds to the mean within the 95% confidence interval (box). Statistical significance was determined using an ANOVA test where *P < 0.05. Measurements have been performed on a minimum of 9 mice taken from 3 independent experiments.
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