Cancer‑specific bivalent promoters featuring low‑level H3K27me3 signals favor active transcription and govern the cancer cell state transitionOA
Bivalent chromatin maintains genes in low‑expression,poised states in embryonic stem cells(ESCs).However,bivalent promoters correlate with the transcriptional activation of oncogenic programs in malignancies,a seemingly contradiction that remains to be resolved.Here,we identify a class of cancer‑specific bivalent promoters(CSBPs)through the integration of a system‑level longitudinal framework.Compared with ESCs,CSBPs are characterized by lower and narrower H3K27me3 deposition alongside abundant H3K4me3,thus permitting the persistent expression of genes critical for cancer stem cell(CSC)formation and maintenance,as exemplified by SOX9.The generation of CSBPs is essentially induced by the acquisition of H3K27me3 during cell state transition,which is mediated by specific binding of PRC2.1 and the de novo recruitment of PRC2.2.Notably,disrupting the bivalency of CSBPs significantly increases H3K4me3 levels,leading to hyperactivation of CSBPs and eventually inhibiting clonal expansion of CSCs and impairing tumorigenesis.Our study not only helps explain the puzzle of transcriptionally active bivalent genes in cancer but also provides insights into the development of therapies targeting phenotypic plasticity.
Fan Yang;Guanlan Fan;Jing Cao;Qiuyan Zhao;Kexiu Guo;Min Liu;Xin Yin;Hongying Zong;Feng Li;Fubing Wang;Jie Xiong
Department of Medical Genetics,School of Basic Medical Sciences,Wuhan University,Wuhan 430071,ChinaDepartment of Gynecology,Zhongnan Hospital of Wuhan University,Wuhan 430071,ChinaDepartment of Gynecology,Zhongnan Hospital of Wuhan University,Wuhan 430071,ChinaDepartment of Gynecology,Zhongnan Hospital of Wuhan University,Wuhan 430071,ChinaDepartment of Medical Genetics,School of Basic Medical Sciences,Wuhan University,Wuhan 430071,ChinaDepartment of Laboratory Medicine,Zhongnan Hospital of Wuhan University,Wuhan 430071,China Hubei Provincial Clinical Research Center for Molecular Diagnostics,Wuhan 430071,ChinaDepartment of Medical Genetics,School of Basic Medical Sciences,Wuhan University,Wuhan 430071,ChinaDemonstration Center for Experimental Basic Medicine Education,Wuhan University,Wuhan 430071,ChinaDepartment of Medical Genetics,School of Basic Medical Sciences,Wuhan University,Wuhan 430071,China Hubei Provincial Key Laboratory of Allergy and Immunology,Wuhan 430071,ChinaDepartment of Laboratory Medicine,Zhongnan Hospital of Wuhan University,Wuhan 430071,China Hubei Provincial Clinical Research Center for Molecular Diagnostics,Wuhan 430071,ChinaDepartment of Immunology,School of Basic Medical Sciences,Wuhan University,Wuhan 430071,China
医药卫生
bivalent promotercell state transitionhistone methylationcancer
《Acta Biochimica et Biophysica Sinica》 2026 (5)
P.989-1007,19
supported by the grants from the National Natural Science Foundation of China(Nos.82573919,32570706,82173137,82403745 and 82403335)the Natural Science Foundation of Hubei Province(No.2022CFA008)the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(No.GZC20231979)the Postdoctoral Project of Hubei Province(No.2024HBBHCXB063)the Program of Excellent Doctor of Zhongnan Hospital of Wuhan University(No.ZNYB2023020)the Hubei Province’s Outstanding Medical Academic Leader Program(Chutian Talent Plan)to F.L.,and the Program of Health Commission of Hubei Province(No.WJ2025M185).
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