TY - JOUR
T1 - PR-DUB maintains the expression of critical genes through FOXK1/2- A nd ASXL1/2/3-dependent recruitment to chromatin and H2AK119ub1 deubiquitination
AU - Kolovos, Petros
AU - Nishimura, Koutarou
AU - Sankar, Aditya
AU - Sidoli, Simone
AU - Cloos, Paul A.
AU - Helin, Kristian
AU - Christensen, Jesper
N1 - Funding Information:
We thank the members of the Helin lab for discussion, technical advice, and support. We thank Ulla Toftegaard for excellent technical assistance. P.K. was supported by the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Rubicon fellowship; 019.162LW.011) and a Marie Curie Individual Fellowship (H2020-MSCA-IF-2017). K.N. was supported by Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers, Japan Society for the Promotion of Science (S2704). The work in the Helin laboratory was supported by the Danish Cancer Society (R167-A10877), the Danish National Research Foundation (DNRF82), the Independent Research Fund Denmark (6153-000005; 7016-00067), The Neye Foundation, through a center grant from the Novo Nordisk Fonden (NNF) to the NNF Center for Stem Cell Biology (NNF17CC0027852), and through the Memorial Sloan Kettering Cancer Center Support Grant (National Institutes of Health P30 CA008748).
Publisher Copyright:
© 2020 Kolovos et al.
PY - 2020/8/3
Y1 - 2020/8/3
N2 - 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.
AB - 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.
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U2 - 10.1101/gr.261016.120
DO - 10.1101/gr.261016.120
M3 - Article
C2 - 32747411
AN - SCOPUS:85090079585
SN - 1088-9051
VL - 30
SP - 1119
EP - 1130
JO - Genome research
JF - Genome research
IS - 8
ER -
