Bernstein Bradley E, Mikkelsen Tarjei S, Xie Xiaohui, Kamal Michael, Huebert Dana J, Cuff James, Fry Ben, Meissner Alex, Wernig Marius, Plath Kathrin, Jaenisch Rudolf, Wagschal Alexandre, Feil Robert, Schreiber Stuart L, Lander Eric S
Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Cell. 2006 Apr 21;125(2):315-26. doi: 10.1016/j.cell.2006.02.041.
The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific modification pattern, termed "bivalent domains," consisting of large regions of H3 lysine 27 methylation harboring smaller regions of H3 lysine 4 methylation. Bivalent domains tend to coincide with TF genes expressed at low levels. We propose that bivalent domains silence developmental genes in ES cells while keeping them poised for activation. We also found striking correspondences between genome sequence and histone methylation in ES cells, which become notably weaker in differentiated cells. These results highlight the importance of DNA sequence in defining the initial epigenetic landscape and suggest a novel chromatin-based mechanism for maintaining pluripotency.
哺乳动物基因组中高度保守的非编码元件（HCNEs）聚集在富含编码对发育至关重要的转录因子（TFs）的基因区域内。这表明富含HCNE的区域可能包含参与发育的关键调控机制。我们通过检测小鼠胚胎干细胞（ES细胞）中56个富含HCNE的大基因座上的组蛋白甲基化来探究这一点。我们鉴定出一种特定的修饰模式，称为“双价结构域”，它由H3赖氨酸27甲基化的大片区域和包含较小H3赖氨酸4甲基化区域组成。双价结构域往往与低水平表达的TF基因重合。我们提出，双价结构域在ES细胞中使发育基因沉默，同时使其保持激活的准备状态。我们还发现ES细胞中的基因组序列与组蛋白甲基化之间存在显著对应关系，而在分化细胞中这种对应关系明显减弱。这些结果突出了DNA序列在定义初始表观遗传格局中的重要性，并提出了一种基于染色质的维持多能性的新机制。
