The phosphatase interactor NIPP1 regulates the occupancy of the histone methyltransferase EZH2 at Polycomb targets.
The phosphatase interactor NIPP1 regulates the occupancy of the histone methyltransferase EZH2 at Polycomb targets.
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DOI：
10.1093/nar/gkq643
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发表时间：
2010-11
影响因子：
14.9
通讯作者：
Bollen M
中科院分区：
文献类型：
--
作者：
Van Dessel N;Beke L;Görnemann J;Minnebo N;Beullens M;Tanuma N;Shima H;Van Eynde A;Bollen M
Polycomb group（PcG）蛋白是干细胞和癌症生物学的关键调节因子。它们主要作为分化和肿瘤抑制基因的阻遏物。一个关键的沉默步骤涉及通过EZH 2对Lys 27（H3 K27）上的组蛋白H3进行三甲基化，EZH 2是Polycomb抑制复合物2（PRC 2）的核心组分。哺乳动物PRC 2复合物最初募集的机制还不清楚。在这里，我们表明，NIPP 1，蛋白质丝氨酸/苏氨酸磷酸酶-1（PP 1）的调节剂，形成一个复杂的PP 1和PRC 2组件染色质。NIPP 1或PP 1的敲低减少了EZH 2与其靶基因的子集的关联，而NIPP 1的过表达导致EZH 2从完全抑制的重新靶向到部分活性的PcG靶点。然而，NIPP 1的PP 1结合突变体（NIPP 1 m）的表达并没有引起EZH 2的重新分布。此外，与DamID技术的染色质结合位点的映射显示，NIPP 1与多个PcG靶基因，包括同源框A簇，而NIPP 1 m显示在这些位点的结合缺陷。我们建议，NIPP 1协会与PcG目标的一个子集在PP 1依赖的方式，从而有助于招聘的PRC 2复杂。
Polycomb group (PcG) proteins are key regulators of stem-cell and cancer biology. They mainly act as repressors of differentiation and tumor-suppressor genes. One key silencing step involves the trimethylation of histone H3 on Lys27 (H3K27) by EZH2, a core component of the Polycomb Repressive Complex 2 (PRC2). The mechanism underlying the initial recruitment of mammalian PRC2 complexes is not well understood. Here, we show that NIPP1, a regulator of protein Ser/Thr phosphatase-1 (PP1), forms a complex with PP1 and PRC2 components on chromatin. The knockdown of NIPP1 or PP1 reduced the association of EZH2 with a subset of its target genes, whereas the overexpression of NIPP1 resulted in a retargeting of EZH2 from fully repressed to partially active PcG targets. However, the expression of a PP1-binding mutant of NIPP1 (NIPP1m) did not cause a redistribution of EZH2. Moreover, mapping of the chromatin binding sites with the DamID technique revealed that NIPP1 was associated with multiple PcG target genes, including the Homeobox A cluster, whereas NIPP1m showed a deficient binding at these loci. We propose that NIPP1 associates with a subset of PcG targets in a PP1-dependent manner and thereby contributes to the recruitment of the PRC2 complex.
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影响因子：
64.5
作者：
Peng JC;Valouev A;Swigut T;Zhang J;Zhao Y;Sidow A;Wysocka J
通讯作者：
Wysocka J
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