Polycomb-like 3 promotes polycomb repressive complex 2 binding to CpG islands and embryonic stem cell self-renewal.
Polycomb-like 3 promotes polycomb repressive complex 2 binding to CpG islands and embryonic stem cell self-renewal.
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DOI：
10.1371/journal.pgen.1002576
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Reiter JF
中科院分区：
文献类型：
--
作者：
Hunkapiller J;Shen Y;Diaz A;Cagney G;McCleary D;Ramalho-Santos M;Krogan N;Ren B;Song JS;Reiter JF
多梳抑制复合物2（PRC 2）使组蛋白H3（H3 K27 me 3）的赖氨酸27三甲基化，以在发育、胚胎干细胞（ESC）分化和癌症的多种生物学转变期间调节基因表达。在这里，我们表明Polycomb-like 3（Pcl 3）是PRC 2的一个组成部分，促进ESC自我更新。使用质谱法，我们确定了Pcl 3作为Suz 12结合伴侣，并通过免疫共沉淀证实了Pcl 3与核心PRC 2组分的相互作用。敲除ESC中的Pcl 3增加自发分化，但不影响早期分化决定，如在畸胎瘤和胚状体中评估的，表明Pcl 3在调节ESC自我更新中具有特定作用。与Pcl 3促进PRC 2功能一致，降低Pcl 3水平降低H3 K27 me 3水平，而过表达Pcl 3增加H3 K27 me 3水平。此外，染色质免疫沉淀和测序（ChIP-seq）揭示，Pcl 3与PRC 2核心组分Suz 12共定位，并且Pcl 3的消耗降低了超过60%的PRC 2靶标的Suz 12结合。Pcl 3 Tudor结构域（一个涉及识别甲基化组蛋白的结构域）内保守残基的突变损害H3 K27 me 3的形成，表明Pcl 3的Tudor结构域对于功能是必需的。我们还表明，Pcl 3和它的paramentum，Pcl 2，存在于不同的PRC 2复合物，但结合许多相同的PRC 2的目标，特别是CpG岛Pcl 3调节。因此，Pcl 3是PRC 2的组分，对于ESC自我更新、组蛋白甲基化和PRC 2向其基因组位点的子集的募集至关重要。胚胎发育需要基因表达的协调变化，以分化特定的细胞类型。基因表达的调节变化对于维持组织稳态和预防癌症也很重要。组蛋白修饰通过影响染色质结构和调节蛋白的募集来控制基因表达。多梳抑制复合物2（PRC 2）催化组蛋白H3上赖氨酸残基的甲基化，这是基因抑制的早期步骤。通过研究PRC 2如何被招募到基因中，我们发现Polycomb样3（Pcl 3）是一种在多种癌症中上调的蛋白质，是PRC 2的一个组成部分，它促进了PRC 2与靶基因的结合和功能。与PRC 2在调节干细胞行为中的作用一致，Pcl 3对于胚胎干细胞自我更新是重要的。因此，Pcl 3是基因阻遏和干细胞自我更新的关键调节剂，其通过控制PRC 2与靶基因的结合而起作用。
Polycomb repressive complex 2 (PRC2) trimethylates lysine 27 of histone H3 (H3K27me3) to regulate gene expression during diverse biological transitions in development, embryonic stem cell (ESC) differentiation, and cancer. Here, we show that Polycomb-like 3 (Pcl3) is a component of PRC2 that promotes ESC self-renewal. Using mass spectrometry, we identified Pcl3 as a Suz12 binding partner and confirmed Pcl3 interactions with core PRC2 components by co-immunoprecipitation. Knockdown of Pcl3 in ESCs increases spontaneous differentiation, yet does not affect early differentiation decisions as assessed in teratomas and embryoid bodies, indicating that Pcl3 has a specific role in regulating ESC self-renewal. Consistent with Pcl3 promoting PRC2 function, decreasing Pcl3 levels reduces H3K27me3 levels while overexpressing Pcl3 increases H3K27me3 levels. Furthermore, chromatin immunoprecipitation and sequencing (ChIP-seq) reveal that Pcl3 co-localizes with PRC2 core component, Suz12, and depletion of Pcl3 decreases Suz12 binding at over 60% of PRC2 targets. Mutation of conserved residues within the Pcl3 Tudor domain, a domain implicated in recognizing methylated histones, compromises H3K27me3 formation, suggesting that the Tudor domain of Pcl3 is essential for function. We also show that Pcl3 and its paralog, Pcl2, exist in different PRC2 complexes but bind many of the same PRC2 targets, particularly CpG islands regulated by Pcl3. Thus, Pcl3 is a component of PRC2 critical for ESC self-renewal, histone methylation, and recruitment of PRC2 to a subset of its genomic sites. Embryonic development requires coordinated changes in gene expression for the differentiation of specific cell types. Regulated changes in gene expression are also important for maintaining tissue homeostasis and preventing cancer. Histone modifications contribute to the control of gene expression by affecting chromatin structure and the recruitment of regulatory proteins. Polycomb repressive complex 2 (PRC2) catalyzes the methylation of a lysine residue on histone H3, an early step in gene repression. By investigating how PRC2 is recruited to genes, we have found that Polycomb-like 3 (Pcl3), a protein upregulated in diverse cancers, is a component of PRC2 that promotes its binding and function at target genes. Consistent with roles for PRC2 in regulating stem cell behaviors, Pcl3 is important for embryonic stem cell self-renewal. Thus, Pcl3 is a critical regulator of gene repression and stem cell self-renewal that acts by controlling PRC2 binding to target genes.
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