Histone marks enable formation of immiscible phase-separated chromatin compartments
Wenjing Sun,
Jiacheng Wang,
Wenqian Liu,
Baixue Tang,
Hongyuan Qu,
Huanxing Su,
Jianwei Wang,
Haitao Li,
Wei Xie,
Pilong Li
Affiliations
Wenjing Sun
State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
Jiacheng Wang
Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
Wenqian Liu
MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
Baixue Tang
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
Hongyuan Qu
MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
Huanxing Su
State Key Laboratory of Mechanism and Quality of Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
Jianwei Wang
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
Haitao Li
MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
Wei Xie
Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; Corresponding author
Pilong Li
State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; Corresponding author
Summary: Eukaryotic chromatin is organized into compartments for gene expression regulation, but the underlying mechanisms remain unclear. Here, we demonstrate that multivalent H3K27me3 and its reader, the CBX7-PRC1 complex, regulate facultative heterochromatin via a phase separation mechanism. Facultative and constitutive heterochromatin represent distinct, coexisting condensates in nuclei. In vitro, H3K27me3- and H3K9me3-marked nucleosomal arrays and their reader complexes can phase separate into immiscible condensates that are analogous to the relationship between facultative and constitutive heterochromatin in vivo. Moreover, overexpression of CBX7-PRC1 causes aberrant chromatin compartmentalization as demonstrated by H3K9me3 CUT&Tag and up-regulation of genes related to cancer, such as acute myeloblastic leukemia (AML). Chromobox 7 (CBX7) inhibitor effectively inhibits cancer cell proliferation, possibly through phase-separation-mediated compartment reorganization. Our data demonstrate how the specificity of compartmentalization is achieved based on the formation of immiscible phase-separated condensates and offer potential epigenetic mechanistic insights into tumor development.
