An essential role for UTX in resolution and activation of bivalent promoters

Shilpa S. Dhar, Sung Hun Lee, Kaifu Chen, Guangjing Zhu, Won Kyung Oh, Kendra Allton, Ohad Gafni, Young Zoon Kim, Alin S. Tomoiga, Michelle Craig Barton, Jacob H. Hanna, Zhibin Wang, Wei Li, Min Gyu Lee

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Trimethylated histone H3 lysine 27 (H3K27me3) is linked to gene silencing, whereas H3K4me3 is associated with gene activation. These two marks frequently co-occupy gene promoters, forming bivalent domains. Bivalency signifies repressed but activatable states of gene expression and can be resolved to active, H3K4me3-prevalent states during multiple cellular processes, including differentiation, development and epithelial mesenchymal transition. However, the molecular mechanism underlying bivalency resolution remains largely unknown. Here, we show that the H3K27 demethylase UTX (also called KDM6A) is required for the resolution and activation of numerous retinoic acid (RA)-inducible bivalent genes during the RA-driven differentiation of mouse embryonic stem cells (ESCs). Notably, UTX loss in mouse ESCs inhibited the RA-driven bivalency resolution and activation of most developmentally critical homeobox (Hox) a-d genes. The UTX-mediated resolution and activation of many bivalent Hox genes during mouse ESC differentiation were recapitulated during RA-driven differentiation of human NT2/D1 embryonal carcinoma cells. In support of the importance of UTX in bivalency resolution, Utx-null mouse ESCs and UTX-depleted NT2/D1 cells displayed defects in RA-driven cellular differentiation. Our results define UTX as a bivalency-resolving histone modifier necessary for stem cell differentiation.

Original languageEnglish (US)
Pages (from-to)3659-3674
Number of pages16
JournalNucleic Acids Research
Volume44
Issue number8
DOIs
StatePublished - May 5 2016

ASJC Scopus subject areas

  • Genetics

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