ChIP-seq analysis of PRC2 core subunits in primary human erythroid progenitor cells

Polycomb Repressive Complex 2 (PRC2) plays crucial roles in transcriptional regulation and stem cell development. However, the context-specific functions associated with alternative subunits remain largely unexplored. Here we show that the related enzymatic subunits EZH1 and EZH2 undergo an expression switch during hematopoiesis. We examine the in vivo stoichiometry of the PRC2 complexes by quantitative proteomics and reveal the existence of an EZH1-SUZ12 sub-complex lacking EED. We provide evidence that EZH1 together with SUZ12 form a non-canonical PRC2 complex, occupy active chromatin domains in the absence of H3K27me3, and positively regulate gene expression. Loss of EZH2 expression leads to global repositioning of EZH1 chromatin occupancy to EZH2 targets. Moreover, we demonstrate that an erythroid-specific enhancer mediates transcriptional activation of EZH1, and a switch from GATA2 to GATA1 controls the developmental EZH1/2 switch by differential association with EZH1 enhancers during erythropoiesis. Thus, the lineage- and developmental stage-specific regulation of PRC2 expression and subunit composition leads to a switch from canonical silencing to non-canonical PRC2 functions during blood stem cell specification.

多梳抑制复合体2（Polycomb Repressive Complex 2，PRC2）在转录调控与干细胞发育过程中发挥关键作用。然而，其与可变亚基相关的情境特异性功能仍未得到充分探索。本研究发现，相关酶促亚基EZH1与EZH2在造血过程中发生表达转换。通过定量蛋白质组学分析PRC2复合物的体内化学计量比，本研究揭示了一种缺乏EED的EZH1-SUZ12亚复合物的存在。本研究证实，EZH1与SUZ12可形成非经典PRC2复合物，在缺乏组蛋白H3赖氨酸27三甲基化（H3K27me3）的情况下结合活性染色质结构域，并正向调控基因表达。EZH2表达缺失会导致EZH1在染色质上的结合位点整体重定位至EZH2的靶基因区域。此外，本研究证实，红系特异性增强子可介导EZH1的转录激活；而在红细胞生成过程中，GATA2向GATA1的转换通过与EZH1增强子的差异性结合，调控发育过程中的EZH1/2表达转换。综上，PRC2表达与亚基组成的谱系及发育阶段特异性调控，可在造血干细胞特化过程中，使PRC2的功能从经典沉默模式转换为非经典功能模式。