PCGF6 Regulates Stem Cell Pluripotency via Super-Enhancer Dependent Chromatin Interactions
Polycomb group (PcG) ring finger protein 6 (PCGF6), known as a core component of the transcription-repressing complexes, PcG, canonically acts as a transcriptional repressor to regulate embryonic development. It also functions as a transcriptional activator to regulate the expression of pluripotency genes. However, the molecular mechanism underlying the activation function of PCGF6 remains to be further understood.
In this study, we aim to explore the molecular mechanism of PCGF6 regulating pluripotency of mouse embryonic stem cells (mESCs). We knocked down Pcgf6 and found that it was not able to maintain the phenotype of mESCs, and the Oct4-GFP positive colonies were significantly reduced in the pre-iPSC reprogramming.
Further, PCGF6 was recruited by OCT4 to multiple super-enhancer (SE) regions upstream of proliferation genes, and promoted their expression levels and then enhanced the proliferation rate of mESCs. We analyzed the expression of SE-associated genes after Pcgf6 knockdown, and found that Pcgf6 knockdown downregulated those genes. By analyzing the promoter capture Hi-C data, we showed that PCGF6 activated those proliferation genes by regulating SE-promoter interactions in 3D chromatin.
Taken together, the role of PCGF6 in regulating pluripotency of mESCs is well established. We provide a potential insight into the new molecular mechanism of PcG components.
本研究中，我们探索了PCGF6调控小鼠胚胎干细胞的多能性的分子机制。我们发现敲低Pcgf6后， mESCs的多能性表型不能维持， pre-iPSC重编程中的Oct4-GFP阳性克隆也显著减少。
更进一步地，我们发现PCGF6能被OCT4招募到许多增殖相关基因上游的超级增强子区域，促进这些基因的表达，进而提高mESCs的增殖速率。Pcgf6的基因敲低也使这些超级增强子相关基因下调。通过分析Promoter capture Hi-C数据，我们还发现这些基因的表达可以通过由PCGF6在三维水平上介导形成的超级增强子-启动子相互作用而被激活。