Department of Biological Sciences and Center for Stem Cell Differentiation, KAIST, Daejeon 305-701, Republic of Korea.
Hum Mol Genet. 2011 Feb 1;20(3):401-12. doi: 10.1093/hmg/ddq476. Epub 2010 Nov 8.
Embryonic stem cells (ESCs) maintain unique epigenetic states to maintain their pluripotency. Differentiation of ESCs into specialized cell types requires changes in these epigenetic states. However, the dynamics of epigenetic marks found in hESCs during differentiation are poorly understood. Here, we report the variation in the dynamics of epigenetic modifications associated with the expression of lineage-specific genes during differentiation of hESCs to hepatocytes in vitro. The promoter regions of pluripotency marker genes characterized by permissive histone marks such as trimethylation of H3 at lysine 4 (H3K4me3) and acetylation of H3 at lysine 9 (H3K9ac) in hESCs were instead enriched with repressive histone marks such as dimethylation of H3 at lysine 9 (H3K9me2), trimethylation of H3 at lysine 9 (H3K9me3) and trimethylation of H3 at lysine 27 (H3K27me3) during differentiation to hepatocytes. Interestingly, expression of definitive endoderm marker genes containing bivalent and non-bivalent domains may be modulated by a marked reduction in H3K27me3 and a significant enhancement of permissive marks such as H3K4me3 and H3K9ac during hESC differentiation. Expression of hepatocyte marker genes regulated by histone modifications was similar to that of pluripotency marker genes. Our findings provide insight into the epigenetic mechanisms regulating expression of developmental genes. Of particular interest, they may be differentially regulated either in a bivalent or non-bivalent domain manner during hESC differentiation.
胚胎干细胞 (ESCs) 保持独特的表观遗传状态以维持其多能性。ESCs 向特化细胞类型的分化需要这些表观遗传状态的改变。然而，在体外分化为肝细胞的过程中，hESC 中发现的表观遗传标记的动态变化仍知之甚少。在这里，我们报告了 hESC 分化为肝细胞过程中与谱系特异性基因表达相关的表观遗传修饰动态变化。在 hESC 中，多能性标记基因的启动子区域富含组蛋白修饰，如 H3 赖氨酸 4 三甲基化 (H3K4me3) 和 H3 赖氨酸 9 乙酰化 (H3K9ac)，这些修饰是允许性的，而在分化为肝细胞时，这些启动子区域富含抑制性组蛋白修饰，如 H3 赖氨酸 9 二甲基化 (H3K9me2)、H3 赖氨酸 9 三甲基化 (H3K9me3) 和 H3 赖氨酸 27 三甲基化 (H3K27me3)。有趣的是，含有双价和非双价结构域的确定内胚层标记基因的表达可能是通过 H3K27me3 的显著减少和允许性标记如 H3K4me3 和 H3K9ac 的显著增强来调节的。受组蛋白修饰调节的肝细胞标记基因的表达与多能性标记基因的表达相似。我们的研究结果提供了对调节发育基因表达的表观遗传机制的深入了解。特别有趣的是，它们可能在 hESC 分化过程中以双价或非双价结构域的方式受到差异调节。
