NIPP1 maintains EZH2 phosphorylation and promoter occupancy at proliferation-related target genes.
NIPP1 maintains EZH2 phosphorylation and promoter occupancy at proliferation-related target genes.
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DOI：
10.1093/nar/gks1255
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发表时间：
2013-01
影响因子：
14.9
通讯作者：
Bollen M
中科院分区：
文献类型：
--
作者：
Minnebo N;Görnemann J;O'Connell N;Van Dessel N;Derua R;Vermunt MW;Page R;Beullens M;Peti W;Van Eynde A;Bollen M
组蛋白甲基转移酶EZH 2通过沉默Polycomb组靶基因来调节细胞增殖和分化。NIPP 1是丝氨酸/苏氨酸蛋白磷酸酶1（PP 1）的核调节因子，参与调节EZH 2在靶基因座的占有率，但其潜在机制尚不清楚。在这里，我们证明了EZH 2的磷酸化的细胞周期蛋白依赖性激酶在Thr 416创建一个对接站点的叉头相关域的NIPP 1。募集的NIPP 1通过抑制PP 1的去磷酸化而使EZH 2能够净磷酸化。因此，EZH 2的NIPP 1结合突变体是低磷酸化的，并且NIPP 1的敲低导致内源性EZH 2的磷酸化降低。相反，PP 1的缺失与EZH 2的过度磷酸化有关。在HeLa细胞中的全基因组启动子结合分析显示，NIPP 1结合突变体显示出与约三分之一的Polycomb靶基因缺乏关联，并且这些基因富含增殖功能。我们的数据将PP 1鉴定为EZH 2磷酸酶，并证明EZH 2与增殖相关靶点的磷酸化调节相关性取决于相关的NIPP 1。
The histone methyltransferase EZH2 regulates cell proliferation and differentiation by silencing Polycomb group target genes. NIPP1, a nuclear regulator of serine/threonine protein phosphatase 1 (PP1), has been implicated in the regulation of EZH2 occupancy at target loci, but the underlying mechanism is not understood. Here, we demonstrate that the phosphorylation of EZH2 by cyclin-dependent kinases at Thr416 creates a docking site for the ForkHead-associated domain of NIPP1. Recruited NIPP1 enables the net phosphorylation of EZH2 by inhibiting its dephosphorylation by PP1. Accordingly, a NIPP1-binding mutant of EZH2 is hypophosphorylated, and the knockdown of NIPP1 results in a reduced phosphorylation of endogenous EZH2. Conversely, the loss of PP1 is associated with a hyperphosphorylation of EZH2. A genome-wide promoter-binding profiling in HeLa cells revealed that the NIPP1-binding mutant shows a deficient association with about a third of the Polycomb target genes, and these are enriched for functions in proliferation. Our data identify PP1 as an EZH2 phosphatase and demonstrate that the phosphorylation-regulated association of EZH2 with proliferation-related targets depends on associated NIPP1.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
EZH1和EZH2通过不同的机制保持抑制性染色质。
影响因子：
16
作者：
Margueron, Raphael;Li, Guohong;Sarma, Kavitha;Blais, Alexandre;Zavadil, Jiri;Woodcock, Christopher L.;Dyniacht, Brian D.;Reinberg, Danny
通讯作者：
Reinberg, Danny
影响因子：
64.5
作者：
Lee, TI;Jenner, RG;Young, RA
通讯作者：
Young, RA
影响因子：
11.4
作者：
Chng, Kern Rei;Chang, Cheng Wei;Cheung, Edwin
通讯作者：
Cheung, Edwin
影响因子：
10.5
作者：
Kaneko, Syuzo;Li, Gang;Reinberg, Danny
通讯作者：
Reinberg, Danny