Functional Dissection of PRC1 Subunits RYBP and YAF2 during Neural Differentiation of Embryonic Stem Cells

Polycomb repressive complex 1 (PRC1) comprises two different complexes: CBX-containing canonical PRC1 (cPRC1) and RYBP/YAF2-containing variant PRC1 (vPRC1). RYBP-vPRC1 or YAF2-vPRC1 catalyzes H2AK119ub through a positive-feedback model; however, whether RYBP and YAF2 have different regulatory functions is still unclear. Here, we show that the expression of RYBP and YAF2 decreases and increases, respectively, during neural differentiation of embryonic stem cells (ESCs). Rybp knockout impairs neural differentiation by activating Wnt signaling and derepressing nonneuroectoderm-associated genes. However, Yaf2 knockout promotes neural differentiation and leads to redistribution of RYBP binding, increases enrichment of RYBP and H2AK119ub on the RYBP-YAF2 cotargeted genes, and prevents ectopic derepression of nonneuroectoderm-associated genes in neural-differentiated cells. Taken together, this study reveals that RYBP and YAF2 function differentially in regulating mESC neural differentiation.

多梳抑制复合体1（Polycomb Repressive Complex 1, PRC1）可分为两类不同的复合物：含CBX的经典型PRC1（cPRC1），以及含RYBP/YAF2的变异型PRC1（vPRC1）。RYBP-vPRC1或YAF2-vPRC1通过正反馈模型催化组蛋白H2A赖氨酸119单泛素化（H2AK119ub）；然而，RYBP与YAF2是否具有不同的调控功能仍未明确。本研究发现，在胚胎干细胞（ESCs）的神经分化过程中，RYBP的表达水平依次降低，而YAF2的表达水平则依次升高。Rybp基因敲除会通过激活Wnt信号通路并解除非神经外胚层相关基因的抑制，损害胚胎干细胞的神经分化能力。与之相反，Yaf2基因敲除可促进神经分化，并导致RYBP结合位点发生重分布，同时增加RYBP与H2AK119ub在RYBP-YAF2共同靶向基因上的富集，还能阻止神经分化细胞中非神经外胚层相关基因的异位去抑制。综上，本研究揭示了RYBP与YAF2在调控小鼠胚胎干细胞神经分化过程中功能存在显著差异。