Department of Genetics, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.
Department of Genetics, Cell Biology and Development, University of Minnesota, and the Masonic Cancer Center, Minneapolis, MN 55455, USA.
Cell Stem Cell. 2018 Feb 1;22(2):235-251.e9. doi: 10.1016/j.stem.2017.12.002. Epub 2018 Jan 11.
Polycomb group proteins regulate self-renewal and differentiation in many stem cell systems. When assembled into two canonical complexes, PRC1 and PRC2, they sequentially deposit H3K27me3 and H2AK119ub histone marks and establish repressive chromatin, referred to as Polycomb domains. Non-canonical PRC1 complexes retain RING1/RNF2 E3-ubiquitin ligases but have unique sets of accessory subunits. How these non-canonical complexes recognize and regulate their gene targets remains poorly understood. Here, we show that the BCL6 co-repressor (BCOR), a member of the PRC1.1 complex, is critical for maintaining primed pluripotency in human embryonic stem cells (ESCs). BCOR depletion leads to the erosion of Polycomb domains at key developmental loci and the initiation of differentiation along endoderm and mesoderm lineages. The C terminus of BCOR regulates the assembly and targeting of the PRC1.1 complex, while the N terminus contributes to BCOR-PRC1.1 repressor function. Our findings advance understanding of Polycomb targeting and repression in ESCs and could apply broadly across developmental systems.
多梳蛋白家族在许多干细胞系统中调节自我更新和分化。当组装成两个规范复合物 PRC1 和 PRC2 时，它们依次沉积 H3K27me3 和 H2AK119ub 组蛋白标记，并建立抑制性染色质，称为多梳域。非规范的 PRC1 复合物保留 RING1/RNF2 E3-泛素连接酶，但具有独特的辅助亚基集。这些非规范复合物如何识别和调节其靶基因仍然知之甚少。在这里，我们表明，BCL6 共抑制因子（BCOR），PRC1.1 复合物的成员，对于维持人类胚胎干细胞（ESC）中的初始多能性至关重要。BCOR 的耗竭导致关键发育基因座上的多梳域侵蚀，并沿着内胚层和中胚层谱系开始分化。BCOR 的 C 末端调节 PRC1.1 复合物的组装和靶向，而 N 末端有助于 BCOR-PRC1.1 抑制子功能。我们的发现推进了对 ESC 中多梳靶标和抑制的理解，并可能广泛适用于发育系统。
