A TET1-PSPC1-Neat1 molecular axis modulates PRC2 functions in controlling stem cell bivalency.
A TET1-PSPC1-Neat1 molecular axis modulates PRC2 functions in controlling stem cell bivalency.
复制标题
DOI：
10.1016/j.celrep.2022.110928
复制
发表时间：
2022-06-07
期刊：
影响因子：
8.8
通讯作者：
Wang, Jianlong
中科院分区：
文献类型：
--
作者：
Huang, Xin;Bashkenova, Nazym;Hong, Yantao;Lyu, Cong;Guallar, Diana;Hu, Zhe;Malik, Vikas;Li, Dan;Wang, Hailin;Shen, Xiaohua;Zhou, Hongwei;Wang, Jianlong
TET 1通过其在胚胎干细胞（ESC）中的催化活性在二价启动子处维持低甲基化。然而，TET 1在调节二价基因方面的非催化活性依赖性功能尚未得到很好的理解。使用蛋白质组学方法，我们绘制了胚胎干细胞中TET 1相互作用组的图谱，并将PSPC 1鉴定为TET 1伴侣。全基因组定位分析表明，PSPC 1与TET 1和Polycomb抑制复合物2（PRC 2）功能相关。我们建立了PSPC 1和TET 1抑制，lncRNA Neat 1激活，二价基因表达。在ESCs中，Neat 1优先结合PSPC 1，并在二价启动子处与PRC 2结合。在胚胎干细胞向外胚层样干细胞（EpiLC）转化过程中，PSPC 1和TET 1在二价基因启动子处维持PRC 2染色质占据，而Neat 1通过促进PRC 2与其mRNA结合来促进某些二价基因的激活。我们的研究证明了TET 1-PSPC 1-Neat 1分子轴在控制干细胞二价中调节PRC 2对染色质和二价基因转录物的结合亲和力。Huang等人使用蛋白质组学和遗传学方法显示TET 1的催化活性独立功能，与paraspeckle组分PSPC 1及其同源lncRNA Neat 1协调，通过调节PRC 2与染色质和二价基因转录物的结合，在幼稚到形成性多能状态转变中动态调节干细胞二价。
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 Huang et al. use proteomics and genetic approaches to show that catalytic activity-independent functions of TET1, coordinated with the paraspeckle components PSPC1 and its cognate lncRNA Neat1, dynamically regulate stem cell bivalency by modulating PRC2 binding to chromatin and bivalent gene transcripts in the naive-to-formative pluripotent state transition.
登录
查看更多内容
影响因子：
23.9
作者：
Dawlaty, Meelad M.;Ganz, Kibibi;Powell, Benjamin E.;Hu, Yueh-Chiang;Markoulaki, Styliani;Cheng, Albert W.;Gao, Qing;Kim, Jongpil;Choi, Sang-Woon;Page, David C.;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf
影响因子：
16
作者：
Cifuentes-Rojas, Catherine;Hernandez, Alfredo J.;Sarma, Kavitha;Lee, Jeannie T.
通讯作者：
Lee, Jeannie T.
影响因子：
23.9
作者：
Fidalgo, Miguel;Huang, Xin;Guallar, Diana;Sanchez-Priego, Carlos;Valdes, Victor Julian;Saunders, Arven;Ding, Junjun;Wu, Wen-Shu;Clavel, Carlos;Wang, Jianlong
通讯作者：
Wang, Jianlong
影响因子：
30.8
作者：
Guallar D;Bi X;Pardavila JA;Huang X;Saenz C;Shi X;Zhou H;Faiola F;Ding J;Haruehanroengra P;Yang F;Li D;Sanchez-Priego C;Saunders A;Pan F;Valdes VJ;Kelley K;Blanco MG;Chen L;Wang H;Sheng J;Xu M;Fidalgo M;Shen X;Wang J
通讯作者：
Wang J
影响因子：
23.9
作者：
Cruz-Molina, Sara;Respuela, Patricia;Rada-Iglesias, Alvaro
通讯作者：
Rada-Iglesias, Alvaro