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.
Bibliographical noteFunding Information:
National Institute of Health (NIH) [R01 GM095659, R01CA157919 to M.G.L.]; Cancer Prevention and Research Institute of Texas (CPRIT) [RP110183 to M.G.L.]; Center for Cancer Epigenetics at MD Anderson Cancer Center [to M.G.L.]; Center for Cancer Epigenetics at MD Anderson Cancer Center [postdoctoral fellowship to S.S.D.]; NIH [R01 HG007538 to W.L.]; CPRIT [RP150292 to W.L.]; NIH [R01 ES025761 to Z.W.]. Funding for open access charge: NIH [R01 GM095659, R01 CA157919].