Conserved, developmentally regulated mechanism couples chromosomal looping and heterochromatin barrier activity at the homeobox gene A locus
Conserved, developmentally regulated mechanism couples chromosomal looping and heterochromatin barrier activity at the homeobox gene A locus
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DOI：
10.1073/pnas.1018279108
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发表时间：
2011-05-03
影响因子：
11.1
通讯作者：
Kim, Tae Hoon
中科院分区：
文献类型：
--
作者：
Kim, Yoon Jung;Cecchini, Katharine R.;Kim, Tae Hoon
不同染色质结构域的建立和分离对于正确的基因组功能是必不可少的。绝缘子蛋白CCCTC结合因子（CTCF）参与创建分离染色质和功能结构域的边界，并通过促进脊椎动物基因组中的染色体环来组织高阶染色质结构。在这里，我们调查的绝缘性能CTCF在人类和小鼠同源框基因A（HOXA）位点。尽管CTCF结合位点上的粘附素加载是成环所需的，但我们发现粘附素对于该位点的染色质屏障活性是不可或缺的。使用小鼠胚胎干细胞在多能和分化的神经元祖细胞状态，我们确定，胚胎干细胞多能性因子OCT 4拮抗在CTCF结合位点的粘附素加载。在定向和分化的神经元祖细胞中OCT4的缺失导致粘附素和染色体成环的加载，这有助于异染色质分配和跨HOXA基因座的选择性基因激活。我们的分析表明，CTCF的染色质屏障活性在进化上是保守的，负责协调建立染色质结构，高阶架构和HOXA基因座的发育表达。
Establishment and segregation of distinct chromatin domains are essential for proper genome function. The insulator protein CCCTC-binding factor (CTCF) is involved in creating boundaries that segregate chromatin and functional domains and in organizing higher-order chromatin structures by promoting chromosomal loops across the vertebrate genome. Here, we investigate the insulation properties of CTCF at the human and mouse homeobox gene A (HOXA) loci. Although cohesin loading at the CTCF binding site is required for looping, we found that cohesin is dispensable for chromatin barrier activity at that site. Using mouse embryonic stem cells in both a pluripotent and differentiated neuronal progenitor state, we determined that embryonic stem cell pluripotency factor OCT4 antagonizes cohesin loading at the CTCF binding site. Loss of OCT4 in the committed and differentiated neuronal progenitor cells results in loading of cohesin and chromosome looping, which contributes to heterochromatin partitioning and selective gene activation across the HOXA locus. Our analysis reveals that chromatin barrier activity of CTCF is evolutionarily conserved and is responsible for the coordinated establishment of chromatin structure, higher-order architecture, and developmental expression of the HOXA locus.