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Uhrf1 regulates active transcriptional marks at bivalent domains in pluripotent stem cells through Setd1a

Kun-Yong Kim,Yoshiaki Tanaka,Juan Su,Bilal Cakir,Yangfei Xiang,Benjamin Patterson,Junjun Ding,Yong-Wook Jung,Ji-Hyun Kim,Eriona Hysolli,Hae-Ri Lee,R. Dajani,Jonghwan Kim,Mei Zhong,Jeong‐Heon Lee,D. Skalnik,J. Lim,G. Sullivan,Jianlong Wang,In-Hyun Park

Published 2018 in Nature Communications

ABSTRACT

Embryonic stem cells (ESCs) maintain pluripotency through unique epigenetic states. When ESCs commit to a specific lineage, epigenetic changes in histones and DNA accompany the transition to specialized cell types. Investigating how epigenetic regulation controls lineage specification is critical in order to generate the required cell types for clinical applications. Uhrf1 is a widely known hemi-methylated DNA-binding protein, playing a role in DNA methylation through the recruitment of Dnmt1 and in heterochromatin formation alongside G9a, Trim28, and HDACs. Although Uhrf1 is not essential in ESC self-renewal, it remains elusive how Uhrf1 regulates cell specification. Here we report that Uhrf1 forms a complex with the active trithorax group, the Setd1a/COMPASS complex, to maintain bivalent histone marks, particularly those associated with neuroectoderm and mesoderm specification. Overall, our data demonstrate that Uhrf1 safeguards proper differentiation via bivalent histone modifications. Uhrf1 is a known regulator of heterochromatin and DNA methylation in embryonic stem cells (ESCs). Here, the authors demonstrate that Uhrf1 acts together with the Set1/COMPASS complex regulator of active transcription to promote H3K4 methylation at bivalent loci and Uhrf1 loss results in disruption of differentiation.

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