A functional crosstalk between the H3K9 methylation writers and their reader HP1 in safeguarding embryonic stem cell identity

Lixia Dong; Huaqi Liao; Linchun Zhao; Jingnan Wang; Congcong Wang; Bowen Wang; Yanqi Sun; Lijun Xu; Yin Xia; Shizhang Ling; Xin Lou; Jinzhong Qin

doi:10.1016/j.stemcr.2023.08.004

A functional crosstalk between the H3K9 methylation writers and their reader HP1 in safeguarding embryonic stem cell identity

Stem Cell Reports. 2023 Sep 12;18(9):1775-1792. doi: 10.1016/j.stemcr.2023.08.004.

Authors

Lixia Dong¹, Huaqi Liao¹, Linchun Zhao¹, Jingnan Wang¹, Congcong Wang¹, Bowen Wang¹, Yanqi Sun¹, Lijun Xu¹, Yin Xia², Shizhang Ling³, Xin Lou⁴, Jinzhong Qin⁵

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, China.
² School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
³ The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, The First Affiliated Hospital (Yijishan Hospital) of Wannan Medical College, Wannan Medical College, Wuhu, China. Electronic address: lingsz@hotmail.com.
⁴ Research Institute of Intelligent Computing, Zhejiang Lab, Hangzhou 311100, China. Electronic address: xin.lou@zhejianglab.edu.cn.
⁵ State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, China; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China. Electronic address: qinjz@nju.edu.cn.

Abstract

Histone H3 lysine 9 (H3K9) methylation, as a hallmark of heterochromatin, has a central role in cell lineage and fate determination. Although evidence of a cooperation between H3K9 methylation writers and their readers has started to emerge, their actual interplay remains elusive. Here, we show that loss of H3K9 methylation readers, the Hp1 family, causes reduced expression of H3K9 methyltransferases, and that this subsequently leads to the exit of embryonic stem cells (ESCs) from pluripotency and a reciprocal gain of lineage-specific characteristics. Importantly, the phenotypes of Hp1-null ESCs can be rescued by ectopic expression of Setdb1, Nanog, and Oct4. Furthermore, Setdb1 ablation results in loss of ESC identity, which is accompanied by a reduction in the expression of Hp1 genes. Together, our data support a model in which the safeguarding of ESC identity involves the cooperation between the H3K9 methylation writers and their readers.

Keywords: G9A; GLP; H3K9 methylation; HP1; SETDB1; crosstalk; embryonic stem cells; germ layer lineages; pluripotency; redundancy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Lineage
Cell Physiological Phenomena*
Chromosomal Proteins, Non-Histone / genetics
Embryonic Stem Cells*
Methylation

Substances

Chromosomal Proteins, Non-Histone