Orford Keith, Kharchenko Peter, Lai Weil, Dao Maria Carlota, Worhunsky David J, Ferro Adam, Janzen Viktor, Park Peter J, Scadden David T
Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Dev Cell. 2008 May;14(5):798-809. doi: 10.1016/j.devcel.2008.04.002.
Throughout development, cell fate decisions are converted into epigenetic information that determines cellular identity. Covalent histone modifications are heritable epigenetic marks and are hypothesized to play a central role in this process. In this report, we assess the concordance of histone H3 lysine 4 dimethylation (H3K4me2) and trimethylation (H3K4me3) on a genome-wide scale in erythroid development by analyzing pluripotent, multipotent, and unipotent cell types. Although H3K4me2 and H3K4me3 are concordant at most genes, multipotential hematopoietic cells have a subset of genes that are differentially methylated (H3K4me2+/me3-). These genes are transcriptionally silent, highly enriched in lineage-specific hematopoietic genes, and uniquely susceptible to differentiation-induced H3K4 demethylation. Self-renewing embryonic stem cells, which restrict H3K4 methylation to genes that contain CpG islands (CGIs), lack H3K4me2+/me3- genes. These data reveal distinct epigenetic regulation of CGI and non-CGI genes during development and indicate an interactive relationship between DNA sequence and differential H3K4 methylation in lineage-specific differentiation.
在整个发育过程中，细胞命运决定被转化为决定细胞身份的表观遗传信息。共价组蛋白修饰是可遗传的表观遗传标记，并被认为在这一过程中发挥核心作用。在本报告中，我们通过分析多能、多能和单能细胞类型，在全基因组范围内评估红细胞发育过程中组蛋白H3赖氨酸4二甲基化（H3K4me2）和三甲基化（H3K4me3）的一致性。虽然H3K4me2和H3K4me3在大多数基因上是一致的，但多能造血细胞有一部分基因存在差异甲基化（H3K4me2+/me3-）。这些基因转录沉默，在谱系特异性造血基因中高度富集，并且对分化诱导的H3K4去甲基化具有独特的敏感性。将H3K4甲基化限制在含有CpG岛（CGI）的基因上的自我更新胚胎干细胞缺乏H3K4me2+/me3-基因。这些数据揭示了发育过程中CGI基因和非CGI基因不同的表观遗传调控，并表明DNA序列与谱系特异性分化中差异H3K4甲基化之间存在相互作用关系。
