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UTX_CHIP_FIBROBLASTS

ABSTRACT: The recent discovery of a large number of histone demethylases suggests a central role for these enzymes in regulating histone methylation dynamics. Histone H3K27 trimethylation (H3K27me3) has been linked to Polycomb Group (PcG) protein-mediated suppression of Hox genes and animal body patterning, X-inactivation and possibly maintenance of embryonic stem (ES) cell identity. An imbalance of H3K27 methylation due to over-expression of the methylase EZH2 has been implicated in metastatic prostate and aggressive breast cancers. Here we show that the related JmjC domain-containing UTX and JMJD3 catalyze demethylation of H3K27me3. UTX is enriched around the transcription start sites of many Hox genes in primary human fibroblasts where Hox genes are differentially expressed, but is selectively excluded from the Hox locus in ES cells in which Hox genes are largely silent. Consistently, RNAi inhibition of UTX led to increased H3K27me3 levels at some Hox gene promoters. Importantly, Morpholino inhibition of a zebrafish UTX homolog resulted in mis-regulation of Hox genes and a striking posterior developmental defect, which was partially rescued by wildtype, but not catalytically inactive human UTX. Taken together, these findings identified a small family of H3K27 demethylases with important, evolutionarily conserved roles in H3K27 methylation regulation and in animal anterior-posterior development. Keywords: organism_part_comparison_design

ORGANISM(S): Homo sapiens

PROVIDER: GSE8855 | GEO | 2007/09/07

SECONDARY ACCESSION(S): PRJNA102209

REPOSITORIES: GEO

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

Project description: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.

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