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首页> 外文期刊>Nucleic Acids Research >The phosphatase interactor NIPP1 regulates the occupancy of the histone methyltransferase EZH2 at Polycomb targets
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The phosphatase interactor NIPP1 regulates the occupancy of the histone methyltransferase EZH2 at Polycomb targets

机译：磷酸酶相互作用因子NIPP1调节组蛋白甲基转移酶EZH2在Polycomb靶标上的占有率

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摘要

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.
机译：polycomb group（PcG）蛋白是干细胞和癌症生物学的关键调节剂。它们主要充当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EZH2（聚梳抑制复合物2（PRC2）的核心成分）在Lys27（H3K27）上对组蛋白H3进行三甲基化。哺乳动物PRC2复合物的初始募集的基础机制尚不清楚。在这里，我们显示NIPP1，蛋白Ser / Thr磷酸酶1（PP1）的调节剂，与染色质上的PP1和PRC2组分形成复合物。敲低NIPP1或PP1降低了EZH2与它的靶基因子集的联系，而NIPP1的过表达导致EZH2从完全受阻的PcG靶标重新靶向。但是，NIPP1的PP1结合突变体（NIPP1m）的表达不会引起EZH2的重新分布。此外，用DamID技术绘制的染色质结合位点的图谱表明，NIPP1与包括Homeobox A簇在内的多个PcG靶基因相关，而NIPP1m在这些基因座上显示出不足的结合。我们建议NIPP1以依赖PP1的方式与PcG目标的一个子集相关联，从而有助于PRC2复合物的募集。

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