PR-DUB safeguards Polycomb repression through H2AK119ub1 restriction

Rui Li; Dandan Huang; Yingying Zhao; Ye Yuan; Xiaoyu Sun; Zhongye Dai; Dawei Huo; Xiaozhi Liu; Kristian Helin; Mulin Jun Li; Xudong Wu

doi:10.1111/cpr.13457

PR-DUB safeguards Polycomb repression through H2AK119ub1 restriction

Rui Li, Dandan Huang, Yingying Zhao, Ye Yuan, Xiaoyu Sun, Zhongye Dai, Dawei Huo, Xiaozhi Liu, Kristian Helin, Mulin Jun Li^*, Xudong Wu^*

^*Corresponding author af dette arbejde

Helin Group

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

2 Citationer (Scopus)

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Abstract

Polycomb group (PcG) proteins are critical chromatin regulators for cell fate control. The mono-ubiquitylation on histone H2AK119 (H2AK119ub1) is one of the well-recognized mechanisms for Polycomb repressive complex 1 (PRC1)-mediated transcription repression. Unexpectedly, the specific H2AK119 deubiquitylation complex composed by additional sex comb-like proteins and BAP1 has also been genetically characterized as Polycomb repressive deubiquitnase (PR-DUB) for unclear reasons. However, it remains a mystery whether and how PR-DUB deficiency affects chromatin states and cell fates through impaired PcG silencing. Here through a careful epigenomic analysis, we demonstrate that a bulk of H2AK119ub1 is diffusely distributed away from promoter regions and their enrichment is positively correlated with PRC1 occupancy. Upon deletion of Asxl2 in mouse embryonic stem cells (ESCs), a pervasive gain of H2AK119ub1 is coincident with increased PRC1 sampling at chromatin. Accordingly, PRC1 is significantly lost from a subset of highly occupied promoters, leading to impaired silencing of associated genes before and after lineage differentiation of Asxl2-null ESCs. Therefore, our study highlights the importance of genome-wide H2AK119ub1 restriction by PR-DUB in safeguarding robust PRC1 deposition and its roles in developmental regulation.

Originalsprog	Engelsk
Artikelnummer	e13457
Tidsskrift	Cell Proliferation
Vol/bind	56
Udgave nummer	10
Antal sider	13
ISSN	0960-7722
DOI	https://doi.org/10.1111/cpr.13457
Status	Udgivet - 2023

Bibliografisk note

Funding Information:
We are grateful to Dr. Guohong Li (IBP, CAS) for sharing the ESCs. And we sincerely thank Drs. Deqing Hu (TMU) and Fei Lan (IBS, Fudan) for helpful discussions. This study was supported by National key research and development programme (2017YFA0504102 to X.W.), the National Natural Science Foundation of China (81772676, 31970579 to X.W., 82103247 to B.W.), the National Key Research and Development Project of Stem Cell and Transformation Research (2019YFA0112100), Key Research Project of Tianjin Education Commission (2020ZD13 to X.W.), the national youth talent support programme and Tianjin Medical University Talent Excellence Program to X.W. Ring1b I53A

Publisher Copyright:
© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.

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10.1111/cpr.13457Licens: CC BY

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Citationsformater

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title = "PR-DUB safeguards Polycomb repression through H2AK119ub1 restriction",

abstract = "Polycomb group (PcG) proteins are critical chromatin regulators for cell fate control. The mono-ubiquitylation on histone H2AK119 (H2AK119ub1) is one of the well-recognized mechanisms for Polycomb repressive complex 1 (PRC1)-mediated transcription repression. Unexpectedly, the specific H2AK119 deubiquitylation complex composed by additional sex comb-like proteins and BAP1 has also been genetically characterized as Polycomb repressive deubiquitnase (PR-DUB) for unclear reasons. However, it remains a mystery whether and how PR-DUB deficiency affects chromatin states and cell fates through impaired PcG silencing. Here through a careful epigenomic analysis, we demonstrate that a bulk of H2AK119ub1 is diffusely distributed away from promoter regions and their enrichment is positively correlated with PRC1 occupancy. Upon deletion of Asxl2 in mouse embryonic stem cells (ESCs), a pervasive gain of H2AK119ub1 is coincident with increased PRC1 sampling at chromatin. Accordingly, PRC1 is significantly lost from a subset of highly occupied promoters, leading to impaired silencing of associated genes before and after lineage differentiation of Asxl2-null ESCs. Therefore, our study highlights the importance of genome-wide H2AK119ub1 restriction by PR-DUB in safeguarding robust PRC1 deposition and its roles in developmental regulation.",

author = "Rui Li and Dandan Huang and Yingying Zhao and Ye Yuan and Xiaoyu Sun and Zhongye Dai and Dawei Huo and Xiaozhi Liu and Kristian Helin and Li, {Mulin Jun} and Xudong Wu",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.",

year = "2023",

doi = "10.1111/cpr.13457",

language = "English",

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T1 - PR-DUB safeguards Polycomb repression through H2AK119ub1 restriction

AU - Li, Rui

AU - Huang, Dandan

AU - Zhao, Yingying

AU - Yuan, Ye

AU - Sun, Xiaoyu

AU - Dai, Zhongye

AU - Huo, Dawei

AU - Liu, Xiaozhi

AU - Helin, Kristian

AU - Li, Mulin Jun

AU - Wu, Xudong

PY - 2023

Y1 - 2023

N2 - Polycomb group (PcG) proteins are critical chromatin regulators for cell fate control. The mono-ubiquitylation on histone H2AK119 (H2AK119ub1) is one of the well-recognized mechanisms for Polycomb repressive complex 1 (PRC1)-mediated transcription repression. Unexpectedly, the specific H2AK119 deubiquitylation complex composed by additional sex comb-like proteins and BAP1 has also been genetically characterized as Polycomb repressive deubiquitnase (PR-DUB) for unclear reasons. However, it remains a mystery whether and how PR-DUB deficiency affects chromatin states and cell fates through impaired PcG silencing. Here through a careful epigenomic analysis, we demonstrate that a bulk of H2AK119ub1 is diffusely distributed away from promoter regions and their enrichment is positively correlated with PRC1 occupancy. Upon deletion of Asxl2 in mouse embryonic stem cells (ESCs), a pervasive gain of H2AK119ub1 is coincident with increased PRC1 sampling at chromatin. Accordingly, PRC1 is significantly lost from a subset of highly occupied promoters, leading to impaired silencing of associated genes before and after lineage differentiation of Asxl2-null ESCs. Therefore, our study highlights the importance of genome-wide H2AK119ub1 restriction by PR-DUB in safeguarding robust PRC1 deposition and its roles in developmental regulation.

AB - Polycomb group (PcG) proteins are critical chromatin regulators for cell fate control. The mono-ubiquitylation on histone H2AK119 (H2AK119ub1) is one of the well-recognized mechanisms for Polycomb repressive complex 1 (PRC1)-mediated transcription repression. Unexpectedly, the specific H2AK119 deubiquitylation complex composed by additional sex comb-like proteins and BAP1 has also been genetically characterized as Polycomb repressive deubiquitnase (PR-DUB) for unclear reasons. However, it remains a mystery whether and how PR-DUB deficiency affects chromatin states and cell fates through impaired PcG silencing. Here through a careful epigenomic analysis, we demonstrate that a bulk of H2AK119ub1 is diffusely distributed away from promoter regions and their enrichment is positively correlated with PRC1 occupancy. Upon deletion of Asxl2 in mouse embryonic stem cells (ESCs), a pervasive gain of H2AK119ub1 is coincident with increased PRC1 sampling at chromatin. Accordingly, PRC1 is significantly lost from a subset of highly occupied promoters, leading to impaired silencing of associated genes before and after lineage differentiation of Asxl2-null ESCs. Therefore, our study highlights the importance of genome-wide H2AK119ub1 restriction by PR-DUB in safeguarding robust PRC1 deposition and its roles in developmental regulation.

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DO - 10.1111/cpr.13457

M3 - Journal article

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