Transcriptomics

Dataset Information

299

RNA-Sequencing of primary myoblasts from mice with a satellite cell specific knockout of the histone demthylase UTX/KDM6A


ABSTRACT: The KDM6 histone demethylases (UTX/KDM6A and JMJD3/KDM6B) mediate removal of repressive histone H3K27me3 marks 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 lacking H3K27-demethylase activity. This suggests that UTX plays an enzyme-independent role in development, and challenges the need for active H3K27-demethylation in vivo. However, the requirement for active H3K27-demethylation in stem cell-mediated tissue regeneration remains untested. Using an inducible mouse knockout that ablates UTX in satellite cells, we show that active H3K27-demethylation is necessary for muscle regeneration. Indeed, loss of UTX in satellite cells blocks myofiber regeneration in both male and female mice. Furthermore, we demonstrate that UTX mediates muscle regeneration through its H3K27-demethylase activity using a chemical inhibitor, and a demethylase-dead UTX knock-in mouse. Mechanistically, dissection of the muscle regenerative process revealed that UTX is required for expression of the transcription factor Myogenin that 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, revealing for the first time that active H3K27-demethylation has a physiological role in vivo. Satellite cells were sorted based on Cre-dependent expression of TdT reporter gene. Sorted UTXmKO or UTX WT satellite cells were then induced to differentiate for 24 hrs. RNA was then isolated and subjected to RNA-Seq analysis.

ORGANISM(S): Mus musculus  

SUBMITTER: Alphonse Chu   Hervé Faralli  Jeffrey F Dilworth 

PROVIDER: E-GEOD-69968 | ArrayExpress | 2016-03-22

SECONDARY ACCESSION(S): GSE69968SRP059609PRJNA287291

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications

UTX demethylase activity is required for satellite cell-mediated muscle regeneration.

Faralli Hervé H   Wang Chaochen C   Nakka Kiran K   Benyoucef Aissa A   Sebastian Soji S   Zhuang Lenan L   Chu Alphonse A   Palii Carmen G CG   Liu Chengyu C   Camellato Brendan B   Brand Marjorie M   Ge Kai K   Dilworth F Jeffrey FJ  

The Journal of clinical investigation 20160321 4


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 d  ...[more]

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