Polycomb Repressive Complex 2 regulates lineage fidelity during embryonic stem cell differentiation.
Polycomb Repressive Complex 2 regulates lineage fidelity during embryonic stem cell differentiation.
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Polycomb Repressive Complex 2 在胚胎干细胞分化过程中调节谱系保真度。
DOI：
10.1371/journal.pone.0110498
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Boyer LA
中科院分区：
文献类型：
--
作者：
Thornton SR;Butty VL;Levine SS;Boyer LA
多梳抑制复合物2（PRC2）催化组蛋白H3赖氨酸27三甲基化（H3K27me3），这是一种与基因抑制相关的表观遗传修饰。H3K27me3富集在胚胎干细胞（ESC）中的大量发育基因的启动子处。H3K27me3的缺失导致ESC不能正确分化，使得难以确定PRC 2在谱系定型过程中的确切作用。此外，虽然研究表明PRC2可以防止DNA甲基化，但这两种表观遗传调节因子如何协调调节谱系程序仍知之甚少。使用维持不同水平的H3K27me3的几个PRC2突变ESC系，我们发现H3K27me3的部分维持允许在ESC定向分化为脊髓运动神经元（SMN）期间谱系基因的适当时间激活。相反，在这些细胞中，指定其他谱系的基因没有被抑制，这表明PRC2也是谱系保真度所必需的。我们还发现，H3K27me3的缺失导致ESC和SMN中PRC2靶区域的DNA甲基化适度增加。我们的研究证明了PRC2在保护谱系决定和保护基因免受不适当的DNA甲基化方面的关键作用。
Polycomb Repressive Complex 2 (PRC2) catalyzes histone H3 lysine 27 tri-methylation (H3K27me3), an epigenetic modification associated with gene repression. H3K27me3 is enriched at the promoters of a large cohort of developmental genes in embryonic stem cells (ESCs). Loss of H3K27me3 leads to a failure of ESCs to properly differentiate, making it difficult to determine the precise roles of PRC2 during lineage commitment. Moreover, while studies suggest that PRC2 prevents DNA methylation, how these two epigenetic regulators coordinate to regulate lineage programs is poorly understood. Using several PRC2 mutant ESC lines that maintain varying levels of H3K27me3, we found that partial maintenance of H3K27me3 allowed for proper temporal activation of lineage genes during directed differentiation of ESCs to spinal motor neurons (SMNs). In contrast, genes that function to specify other lineages failed to be repressed in these cells, suggesting that PRC2 is also necessary for lineage fidelity. We also found that loss of H3K27me3 leads to a modest gain in DNA methylation at PRC2 target regions in both ESCs and in SMNs. Our study demonstrates a critical role for PRC2 in safeguarding lineage decisions and in protecting genes against inappropriate DNA methylation.
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