PR-DUB maintains the expression of critical genes through FOXK1/2- and ASXL1/2/3-dependent recruitment to chromatin and H2AK119ub1 deubiquitination
- Petros Kolovos1,2,3,6,
- Koutarou Nishimura1,2,4,6,
- Aditya Sankar1,2,6,
- Simone Sidoli5,
- Paul A. Cloos1,2,
- Kristian Helin1,2,4 and
- Jesper Christensen1,2
- 1Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark;
- 2The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, DK-2200 Copenhagen N, Denmark;
- 3Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus Dragana, 68100, Alexandroupolis, Greece;
- 4Cell Biology Program and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York 10065, USA;
- 5Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA
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↵6 These authors contributed equally to this work.
Abstract
Polycomb group proteins are important for maintaining gene expression patterns and cell identity in metazoans. The mammalian Polycomb repressive deubiquitinase (PR-DUB) complexes catalyze removal of monoubiquitination on lysine 119 of histone H2A (H2AK119ub1) through a multiprotein core comprised of BAP1, HCFC1, FOXK1/2, and OGT in combination with either of ASXL1, 2, or 3. Mutations in PR-DUB components are frequent in cancer. However, mechanistic understanding of PR-DUB function in gene regulation is limited. Here, we show that BAP1 is dependent on the ASXL proteins and FOXK1/2 in facilitating gene activation across the genome. Although PR-DUB was previously shown to cooperate with PRC2, we observed minimal overlap and functional interaction between BAP1 and PRC2 in embryonic stem cells. Collectively, these results demonstrate that PR-DUB, by counteracting accumulation of H2AK119ub1, maintains chromatin in an optimal configuration ensuring expression of genes important for general functions such as cell metabolism and homeostasis.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.261016.120.
- Received January 10, 2020.
- Accepted July 10, 2020.
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