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; Haelim Lee; Rana Dajani; Jonghwan Kim; Mei Zhong; Jeong-Heon Lee; David Skalnik; Jeong Mook Lim; Gareth J Sullivan; Jianlong Wang; In-Hyun Park

doi:10.1038/s41467-018-04818-0

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

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

Authors

Kun-Yong Kim¹, Yoshiaki Tanaka¹, Juan Su^{1

2}, Bilal Cakir¹, Yangfei Xiang¹, Benjamin Patterson¹, Junjun Ding³, Yong-Wook Jung⁴, Ji-Hyun Kim¹, Eriona Hysolli¹, Haelim Lee¹, Rana Dajani^{5

6}, Jonghwan Kim⁷, Mei Zhong⁸, Jeong-Heon Lee⁹, David Skalnik⁹, Jeong Mook Lim¹⁰, Gareth J Sullivan^{11

12}, Jianlong Wang³, In-Hyun Park¹³

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
CCAAT-Enhancer-Binding Proteins
Cellular Reprogramming / genetics*
Cellular Reprogramming Techniques
Chimera
DNA Methylation / physiology
Epigenesis, Genetic
Female
Fibroblasts
Gene Knockout Techniques
HEK293 Cells
Histone Code / genetics*
Histone-Lysine N-Methyltransferase / genetics
Histone-Lysine N-Methyltransferase / isolation & purification
Histone-Lysine N-Methyltransferase / metabolism*
Histones / metabolism
Humans
Male
Mesoderm / cytology
Mesoderm / physiology
Mice
Mouse Embryonic Stem Cells
Neural Plate / cytology
Neural Plate / physiology
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Primary Cell Culture
Recombinant Proteins / genetics
Recombinant Proteins / isolation & purification
Recombinant Proteins / metabolism
Ubiquitin-Protein Ligases

Substances

CCAAT-Enhancer-Binding Proteins
Histones
Nuclear Proteins
Recombinant Proteins
Histone-Lysine N-Methyltransferase
Nsccn1 protein, mouse
Setd1A protein, human
Ubiquitin-Protein Ligases
Uhrf1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding