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Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):E7949-E7958. doi: 10.1073/pnas.1711158114. Epub 2017 Aug 30.

Role of remodeling and spacing factor 1 in histone H2A ubiquitination-mediated gene silencing.

Author information

1
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294.
2
Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
3
University of Chinese Academy of Sciences, Beijing 100049, China.
4
Department of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90033.
5
School of Biological Sciences, Nanyang Technological University, Singapore 637551.
6
Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294.
7
Division of Preventive Medicine, University of Alabama at Birmingham Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294.
8
School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332.
9
Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G 1L7.
10
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada M5G 1L7.
11
Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294; cchang@uab.edu luojianj@ibp.ac.cn ltchow@uab.edu hbwang@uab.edu.
12
Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; cchang@uab.edu luojianj@ibp.ac.cn ltchow@uab.edu hbwang@uab.edu.
13
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294; cchang@uab.edu luojianj@ibp.ac.cn ltchow@uab.edu hbwang@uab.edu.

Abstract

Posttranslational histone modifications play important roles in regulating chromatin-based nuclear processes. Histone H2AK119 ubiquitination (H2Aub) is a prevalent modification and has been primarily linked to gene silencing. However, the underlying mechanism remains largely obscure. Here we report the identification of RSF1 (remodeling and spacing factor 1), a subunit of the RSF complex, as a H2Aub binding protein, which mediates the gene-silencing function of this histone modification. RSF1 associates specifically with H2Aub, but not H2Bub nucleosomes, through a previously uncharacterized and obligatory region designated as ubiquitinated H2A binding domain. In human and mouse cells, genes regulated by RSF1 overlap significantly with those controlled by RNF2/Ring1B, the subunit of Polycomb repressive complex 1 (PRC1) which catalyzes the ubiquitination of H2AK119. About 82% of H2Aub-enriched genes, including the classic PRC1 target Hox genes, are bound by RSF1 around their transcription start sites. Depletion of H2Aub levels by Ring1B knockout results in a significant reduction of RSF1 binding. In contrast, RSF1 knockout does not affect RNF2/Ring1B or H2Aub levels but leads to derepression of H2Aub target genes, accompanied by changes in H2Aub chromatin organization and release of linker histone H1. The action of RSF1 in H2Aub-mediated gene silencing is further demonstrated by chromatin-based in vitro transcription. Finally, RSF1 and Ring1 act cooperatively to regulate mesodermal cell specification and gastrulation during Xenopus early embryonic development. Taken together, these data identify RSF1 as a H2Aub reader that contributes to H2Aub-mediated gene silencing by maintaining a stable nucleosome pattern at promoter regions.

KEYWORDS:

H2A ubiquitination; H2Aub binding protein; PRC1; RSF1; transcription repression

PMID:
28855339
PMCID:
PMC5617306
DOI:
10.1073/pnas.1711158114
[Indexed for MEDLINE]
Free PMC Article

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