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一个 TET1-PSPC1-Neat1 分子轴调节 PRC2 功能以控制干细胞二价性。

A TET1-PSPC1-Neat1 molecular axis modulates PRC2 functions in controlling stem cell bivalency.

机构信息

Department of Medicine, Columbia Center for Human Development, Columbia Stem Cell Initiative, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.

Tsinghua Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.

出版信息

Cell Rep. 2022 Jun 7;39(10):110928. doi: 10.1016/j.celrep.2022.110928.

DOI:10.1016/j.celrep.2022.110928
PMID:35675764
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9214724/
Abstract

TET1 maintains hypomethylation at bivalent promoters through its catalytic activity in embryonic stem cells (ESCs). However, TET1 catalytic activity-independent function in regulating bivalent genes is not well understood. Using a proteomics approach, we map the TET1 interactome in ESCs and identify PSPC1 as a TET1 partner. Genome-wide location analysis reveals that PSPC1 functionally associates with TET1 and Polycomb repressive complex-2 (PRC2). We establish that PSPC1 and TET1 repress, and the lncRNA Neat1 activates, bivalent gene expression. In ESCs, Neat1 is preferentially bound to PSPC1 alongside its PRC2 association at bivalent promoters. During the ESC-to-epiblast-like stem cell (EpiLC) transition, PSPC1 and TET1 maintain PRC2 chromatin occupancy at bivalent gene promoters, while Neat1 facilitates the activation of certain bivalent genes by promoting PRC2 binding to their mRNAs. Our study demonstrates a TET1-PSPC1-Neat1 molecular axis that modulates PRC2-binding affinity to chromatin and bivalent gene transcripts in controlling stem cell bivalency.

摘要

TET1 通过其在胚胎干细胞 (ESC) 中的催化活性维持二价启动子的低甲基化。然而,TET1 在调节二价基因方面的催化活性非依赖性功能尚未得到很好的理解。我们使用蛋白质组学方法在 ESC 中绘制了 TET1 的互作组,并鉴定了 PSPC1 为 TET1 的伴侣。全基因组定位分析表明 PSPC1 与 TET1 和多梳抑制复合物-2 (PRC2) 具有功能相关性。我们确定 PSPC1 和 TET1 抑制,而长非编码 RNA Neat1 激活二价基因的表达。在 ESC 中,Neat1 与 PSPC1 及其在二价启动子处的 PRC2 缔合优先结合。在 ESC 到类胚胎干细胞 (EpiLC) 过渡期间,PSPC1 和 TET1 维持 PRC2 染色质在二价基因启动子处的占有率,而 Neat1 通过促进 PRC2 与其 mRNA 的结合来促进某些二价基因的激活,从而发挥作用。我们的研究表明,TET1-PSPC1-Neat1 分子轴在调节干细胞二价性方面调节 PRC2 与染色质和二价基因转录本的结合亲和力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/825d/9214724/2e0b21c91446/nihms-1814645-f0007.jpg
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