UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity

Thursday, October 11, 2012 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center, Building 45	NIDDK	STEMCELL-6

Authors

• C Wang
• JE Lee
• YW Cho
• Y Xiao
• Q Jin
• C Liu
• K Ge

Abstract

To investigate the role of histone H3K27 demethylase UTX in embryonic stem (ES) cell differentiation, we have generated UTX knockout (KO) and enzyme-dead knockin ES cells. Deletion of UTX in ES cells has no effect on global H3K27me3 level, Hox gene expression, or ES cell self-renewal. However, UTX KO cells show severe defects in mesoderm differentiation and induction of Brachyury, a transcription factor essential for mesoderm development. Surprisingly, UTX regulates mesoderm differentiation and Brachyury expression independent of its enzymatic activity. The homologous UTY, which lacks demethylase activity, compensates for the loss of UTX in regulating Brachyury expression. UTX and UTY bind directly to Brachyury promoter and are required for Wnt/beta-catenin signaling-induced Brachyury expression in ES cells. Finally, deletion of UTX in mice leads to severe defects in both Brachyury expression and embryonic development of mesoderm-derived posterior notochord, cardiac and hematopoietic tissues. These results indicate that UTX controls mesoderm differentiation and Brachyury expression independent of its H3K27 demethylase activity.

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