Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Institute of Hematology, Zhejiang University, Hangzhou, 310058, China.
Nat Commun. 2021 May 14;12(1):2829. doi: 10.1038/s41467-021-22871-0.
Polycomb group (PcG) proteins maintain cell identity by repressing gene expression during development. Surprisingly, emerging studies have recently reported that a number of PcG proteins directly activate gene expression during cell fate determination process. However, the mechanisms by which they direct gene activation in pluripotency remain poorly understood. Here, we show that Phc1, a subunit of canonical polycomb repressive complex 1 (cPRC1), can exert its function in pluripotency maintenance via a PRC1-independent activation of Nanog. Ablation of Phc1 reduces the expression of Nanog and overexpression of Nanog partially rescues impaired pluripotency caused by Phc1 depletion. We find that Phc1 interacts with Nanog and activates Nanog transcription by stabilizing the genome-wide chromatin interactions of the Nanog locus. This adds to the already known canonical function of PRC1 in pluripotency maintenance via a PRC1-dependent repression of differentiation genes. Overall, our study reveals a function of Phc1 to activate Nanog transcription through regulating chromatin architecture and proposes a paradigm for PcG proteins to maintain pluripotency.
多梳抑制复合物（PcG）蛋白通过在发育过程中抑制基因表达来维持细胞身份。令人惊讶的是，最近的一些新兴研究报告称，许多 PcG 蛋白在细胞命运决定过程中直接激活基因表达。然而，它们在多能性中指导基因激活的机制仍知之甚少。在这里，我们表明，Phc1 是典型多梳抑制复合物 1（cPRC1）的一个亚基，可通过非依赖于 PRC1 的 Nanog 激活来发挥其在多能性维持中的功能。Phc1 的缺失会降低 Nanog 的表达，而过表达 Nanog 可部分挽救由 Phc1 耗竭引起的多能性受损。我们发现 Phc1 与 Nanog 相互作用，并通过稳定 Nanog 基因座的全基因组染色质相互作用来激活 Nanog 转录。这增加了 PRC1 通过依赖于 PRC1 的分化基因抑制来维持多能性的已知功能。总的来说，我们的研究揭示了 Phc1 通过调节染色质结构激活 Nanog 转录的功能，并提出了 PcG 蛋白维持多能性的范例。
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