Cohesin Mediates Chromatin Interactions That Regulate Mammalian β-globin Expression
Cohesin Mediates Chromatin Interactions That Regulate Mammalian β-globin Expression
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DOI：
10.1074/jbc.m110.207365
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发表时间：
2011-05-20
影响因子：
4.8
通讯作者：
Yokomori, Kyoko
中科院分区：
文献类型：
--
作者：
Chien, Richard;Zeng, Weihua;Yokomori, Kyoko
β-珠蛋白基因座在分化的红系细胞中经历动态染色质相互作用变化，这被认为对于适当的珠蛋白基因表达是重要的。然而，其潜在机制尚不清楚。CCCTC结合因子CTCF在基因座的5'和3'边界与绝缘子元件结合，但这些位点被证明是珠蛋白基因激活的关键。我们发现，诱导分化后，粘着蛋白和粘着蛋白加载因子Nipped-B样（Nippl）结合到CTCF绝缘子和远端增强子区域的基因座控制区（LCR），以及在分化后经历激活的特定靶球蛋白基因。乳头依赖性粘附素结合对于CTCF绝缘子元件之间以及LCR远端增强子与靶基因之间的长距离染色质相互作用至关重要。我们发现，后者的相互作用是很重要的珠蛋白基因表达在体内和体外。此外，结果表明，这种与基因调控相关的粘着蛋白介导的染色质相互作用对杂合突变引起的Nipbl部分减少敏感。这提供了第一个直接的证据表明，Nippl单倍不足影响粘着蛋白介导的染色质相互作用和基因表达。我们的研究结果表明，动态Nippl/cohesin结合是至关重要的发育染色质组织和LCR在哺乳动物细胞中的基因激活功能。
The beta-globin locus undergoes dynamic chromatin interaction changes in differentiating erythroid cells that are thought to be important for proper globin gene expression. However, the underlying mechanisms are unclear. The CCCTC-binding factor, CTCF, binds to the insulator elements at the 5' and 3' boundaries of the locus, but these sites were shown to be dispensable for globin gene activation. We found that, upon induction of differentiation, cohesin and the cohesin loading factor Nipped-B-like (Nipbl) bind to the locus control region (LCR) at the CTCF insulator and distal enhancer regions as well as at the specific target globin gene that undergoes activation upon differentiation. Nipbl-dependent cohesin binding is critical for long-range chromatin interactions, both between the CTCF insulator elements and between the LCR distal enhancer and the target gene. We show that the latter interaction is important for globin gene expression in vivo and in vitro. Furthermore, the results indicate that such cohesin-mediated chromatin interactions associated with gene regulation are sensitive to the partial reduction of Nipbl caused by heterozygous mutation. This provides the first direct evidence that Nipbl haploinsufficiency affects cohesin-mediated chromatin interactions and gene expression. Our results reveal that dynamic Nipbl/cohesin binding is critical for developmental chromatin organization and the gene activation function of the LCR in mammalian cells.