Epigenetics of developmental regulation of mammalian genes

我们在包括β-珠蛋白基因座在内的人类11号染色体的300 Kb范围内以高分辨率确定了表观遗传修饰特征和染色质结构。单甲基化H3 K4、H3 K9和H3 K36广泛分布，特别是K4单甲基化标记LCR增强子区域。二-和三-甲基化形式的H3出现在高度转录的珠蛋白基因中，以单甲基标记为代价，与酶促转化的转录偶联机制一致。然而，H3 K36三甲基化在转录的编码区以及基因座的非编码区中被强烈检测到，这使得我们提出在哺乳动物中H3 K36三甲基化是在任何水平转录的序列上的稳定标记。有趣的是，大多数表观遗传和染色质结构特征在绝缘子因子CTCF相互作用的球蛋白结构域的假定边界处没有发生转变，这引发了有关边界功能的问题。在这个节骨眼上，似乎在这个不断发展的领域需要新的增强子-绝缘子拮抗模型。我们正在扩展这些研究，包括正常的红系前体细胞以下基因座广泛的表观遗传修饰在分化过程中。

We determined epigenetic modification signatures and chromatin structure at high resolution across 300 Kb of human chromosome 11 including the beta-globin locus. Mono-methylated H3 K4, H3 K9 and H3 K36 were broadly distributed, with K4 mono-methylation, in particular, marking the LCR enhancer region. Di- and tri-methylated forms of H3 appeared at highly transcribed globin genes at the expense of the mono-methyl mark, consistent with a transcription coupled mechanism of enzymatic conversion. However, H3 K36 tri-methylation was strongly detected in transcribed coding as well as non-coding regions of the locus leading us to propose that in mammals H3 K36 tri-methylation is a stable mark on sequences transcribed at any level. Interestingly, most epigenetic and chromatin structural features did not undergo transitions at the presumed borders of the globin domain where the insulator factor CTCF interacts, raising questions about the function of the borders. At this juncture, it seems that new models of enhancer-insulator antagonism are needed in this evolving field. We are extending these studies to include normal erythroid precursor cells by following locus wide epigenetic modification during differentiation.