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Nat Commun. 2018 Jul 3;9(1):2583. doi: 10.1038/s41467-018-04818-0.

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

Author information

1
Department of Genetics, Yale Stem Cell Center, Yale Child Study Center, Yale School of Medicine, New Haven, CT, 06520, USA.
2
Department of Cell Biology, the Second Military Medical University, 200433, Shanghai, China.
3
Department of Cell, Developmental and Regenerative Biology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
4
Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, 06135, Republic of Korea.
5
Department of Biology and Biotechnology, Hashemite University, Zarqa, 13115, Jordan.
6
Radcliffe Institute for Advanced Studies, Harvard University, Cambridge,, 02138 MA, USA.
7
Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, Center for Systems and Synthetic Biology, the University of Texas at Austin, Austin, TX, 78712, USA.
8
Department of Cell Biology, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, 06520, USA.
9
Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202, USA.
10
Department of Agricultural Biotechnology, Seoul National University, Seoul, 08826, Korea.
11
Department of Molecular Medicine, Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, 0372, Oslo, Norway.
12
Norwegian Center for Stem Cell Research, Institute of Immunology, Oslo University Hospital and University of Oslo, 0372, Oslo, Norway.
13
Department of Genetics, Yale Stem Cell Center, Yale Child Study Center, Yale School of Medicine, New Haven, CT, 06520, USA. inhyun.park@yale.edu.

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.

PMID:
29968706
PMCID:
PMC6030064
DOI:
10.1038/s41467-018-04818-0
[Indexed for MEDLINE]
Free PMC Article

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