Thornton Seraphim R, Butty Vincent L, Levine Stuart S, Boyer Laurie A
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
BioMicro Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
PLoS One. 2014 Oct 21;9(10):e110498. doi: 10.1371/journal.pone.0110498. eCollection 2014.
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.
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在胚胎干细胞（ESC）中大量发育基因的启动子处富集。H3K27me3的缺失导致ESC无法正常分化，这使得确定PRC2在细胞谱系定向分化过程中的精确作用变得困难。此外，虽然研究表明PRC2可防止DNA甲基化，但这两种表观遗传调节因子如何协调以调控细胞谱系程序仍知之甚少。利用几种维持不同水平H3K27me3的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）的过程中适时激活谱系基因。相比之下，在这些细胞中，决定其他细胞谱系的基因未能被抑制，这表明PRC2对于细胞谱系保真度也是必需的。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在保障细胞谱系决定以及保护基因免受不适当DNA甲基化方面的关键作用。
