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

Mol Cell

State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Cell Biology, Tianjin Medical University, Qixiangtai Road 22, Tianjin 300070, China; Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Key Laboratory of Epigenetics for Organ Development of Premature Infants, Tianjin 300450, China. Electronic address:

Published: March 2022

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.

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http://dx.doi.org/10.1016/j.molcel.2022.01.027DOI Listing

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