Histone demethylase complexes KDM3A and KDM3B cooperate with OCT4/SOX2 to define a pluripotency gene regulatory network

• DOI: 10.1096/fj.202100230r
• Publication Date: 2021-05-27T10:06:39Z
• Authors: Zhenshuo Zhu; Xiaolong Wu; Qun Li; Juqing Zhang; Shuai Yu; Qiaoyan Shen; Zhe Zhou; Qin Pan; Wei Yue; Dezhe Qin; Ying Zhang; Wenxu Zhao; Rui Zhang; Sha Peng; Na Li; Shiqiang Zhang; Anmin Lei; Yi‐Liang Miao; Zhonghua Liu; Xingqi Chen; Huayan Wang; Mingzhi Liao; Jinlian Hua
• Keywords: 570; Jumonji Domain-Containing Histone Demethylases; 0303 health sciences; histone demethylase complexes; Swine; SOXB1 Transcription Factors; KDM3A/3B; Induced Pluripotent Stem Cells; 500; Gene Expression Regulation, Developmental; DNA Methylation; pluripotency; Epigenesis, Genetic; 03 medical and health sciences; H3K9 methylation; Animals; Gene Regulatory Networks; Octamer Transcription Factor-3

The pluripotency gene regulatory network of porcine induced pluripotent stem cells(piPSCs), especially in epigenetics, remains elusive. To determine the biological function of epigenetics, we cultured piPSCs in different culture conditions. We found that activation of pluripotent gene- and pluripotency-related pathways requires the erasure of H3K9 methylation modification which was further influenced by mouse embryonic fibroblast (MEF) served feeder. By dissecting the dynamic change of H3K9 methylation during loss of pluripotency, we demonstrated that the H3K9 demethylases KDM3A and KDM3B regulated global H3K9me2/me3 level and that their co-depletion led to the collapse of the pluripotency gene regulatory network. Immunoprecipitation-mass spectrometry (IP-MS) provided evidence that KDM3A and KDM3B formed a complex to perform H3K9 demethylation. The genome-wide regulation analysis revealed that OCT4 (O) and SOX2 (S), the core pluripotency transcriptional activators, maintained the pluripotent state of piPSCs depending on the H3K9 hypomethylation. Further investigation revealed that O/S cooperating with histone demethylase complex containing KDM3A and KDM3B promoted pluripotency genes expression to maintain the pluripotent state of piPSCs. Together, these data offer a unique insight into the epigenetic pluripotency network of piPSCs.