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Dr. Shen, Xiao-Hua 沈晓骅
Professor of Center for Stem Cell Research, School of Medicine, Tsinghua University, China

Abstract:

Epigenetic mechanisms control stem cell differentiation and organogenesis by influencing chromatin structure and gene expression programs. Epigenetic deregulation contributes to disease. Polycomb group (PcG) proteins are central players in mammalian development, and are often linked to human cancer. An initial step in PcG regulation of gene expression is the targeting of a protein complex named Polycomb repressive complex 2 (PRC2) to specific regions of chromatin to establish the repressive trimethylation mark on histone H3 lysine 27 (H3K27me3). H3K27me3 and PRC2 have been implicated in maintaining the pluripotent state of embryonic stem (ES) cells. To study the function and regulation of PRC2 in the epigenetic regulation of stem cell pluripotency, we constructed a core PRC2 interaction network in ES cells. We identified EZH1 as an alternative H3K27 methyltransferase, and JMJ (JUMONJI or JARID2) and MTF2 (or PCL2) as novel regulators of PRC2. By isolation and characterization of knockout ES cells lacking core PRC2 components, we demonstrate critical roles for PRC2 in execution of pluripotency rather than maintenance of stem cell state. Our work highlights the importance of chromatin dynamics in cellular differentiation, and suggests greater complexity in the composition of the Polycomb repressive complex 2 (PRC2), which may render epigenetic specificity during cell-fate transitions.