CpG island reconfiguration for the establishment and synchronization of polycomb functions upon exit from naive pluripotency

Dawei Huo, Zhaowei Yu, Rui Li, Meihan Gong, Simone Sidoli, Xukun Lu, Yuying Hou, Zhongye Dai, Yu Kong, Guifen Liu, Ole N. Jensen, Wei Xie, Kristian Helin, Chaoyang Xiong, Guohong Li, Yong Zhang, Xudong Wu

Research output: Contribution to journalArticlepeer-review

Abstract

Polycomb group (PcG) proteins are essential for post-implantation development by depositing repressive histone modifications at promoters, mainly CpG islands (CGIs), of developmental regulator genes. However, promoter PcG marks are erased after fertilization and de novo established in peri-implantation embryos, coinciding with the transition from naive to primed pluripotency. Nevertheless, the molecular basis for this establishment remains unknown. In this study, we show that the expression of the long KDM2B isoform (KDM2BLF), which contains the demethylase domain, is specifically induced at peri-implantation and that its H3K36me2 demethylase activity is required for PcG enrichment at CGIs. Moreover, KDM2BLF interacts with BRG1/BRM-associated factor (BAF) and stabilizes BAF occupancy at CGIs for subsequent gain of accessibility, which precedes PcG enrichment. Consistently, KDM2BLF inactivation results in significantly delayed post-implantation development. In summary, our data unveil dynamic chromatin configuration of CGIs during exit from naive pluripotency and provide a conceptual framework for the spatiotemporal establishment of PcG functions.

Original languageEnglish (US)
Pages (from-to)1169-1185.e7
JournalMolecular Cell
Volume82
Issue number6
DOIs
StatePublished - Mar 17 2022

Keywords

  • BRG1
  • CpG islands
  • H2AK119ub
  • H3K27me3
  • H3K36me2
  • SWI/SNF
  • accessibility
  • demethylation
  • polycomb
  • post-implantation development

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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