Ghirlando Rodolfo, Giles Keith, Gowher Humaira, Xiao Tiaojiang, Xu Zhixiong, Yao Hongjie, Felsenfeld Gary
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Key Diseases, National Insitute of Health, 9000 Rockville Pike, Bethesda, MD 20892-0540, USA.
Biochim Biophys Acta. 2012 Jul;1819(7):644-51. doi: 10.1016/j.bbagrm.2012.01.016. Epub 2012 Feb 2.
The DNA sequence elements called insulators have two basic kinds of properties. Barrier elements block the propagation of heterochromatic structures into adjacent euchromatin. Enhancer blocking elements interfere with interaction between an enhancer and promoter when placed between them. We have dissected a compound insulator element found at the 5' end of the chicken β-globin locus, which possesses both activities. Barrier insulation is mediated by two kinds of DNA binding proteins: USF1/USF2, a heterodimer which recruits multiple enzyme complexes capable of marking histone on adjacent nucleosomes with 'activating' marks, and Vezf1, which protects against DNA methylation. We have found that the heterochromatic region upstream of the insulator element is maintained in its silent state by a dicer-dependent mechanism, suggesting a mechanism for Vezf1 function in the insulator. Enhancer blocking function in the β-globin insulator element is conferred by a binding site for CTCF. Consistent with this property, CTCF binding was found some years ago to be essential for imprinted expression at the Igf2/H19 locus. Work in many laboratories has since demonstrated that CTCF helps stabilize long-range interactions in the nucleus. We have recently shown that in the case of the human insulin locus such an interaction, over a distance of ~300kb, can result in stimulation of a target gene which itself is important for insulin secretion. This article is part of a Special Issue entitled: Chromatin in time and space.
被称为绝缘子的DNA序列元件具有两种基本特性。屏障元件可阻止异染色质结构向相邻常染色质的传播。增强子阻断元件置于增强子和启动子之间时，会干扰它们之间的相互作用。我们剖析了在鸡β-珠蛋白基因座5'端发现的一种复合绝缘子元件，它具有这两种活性。屏障绝缘由两种DNA结合蛋白介导：USF1/USF2，一种异二聚体，可募集多种能够在相邻核小体上用“激活”标记标记组蛋白的酶复合物，以及Vezf1，它可防止DNA甲基化。我们发现，绝缘子元件上游的异染色质区域通过一种依赖于Dicer的机制维持其沉默状态，这提示了Vezf1在绝缘子中发挥功能的一种机制。β-珠蛋白绝缘子元件中的增强子阻断功能由CTCF的一个结合位点赋予。与此特性一致，几年前发现CTCF结合对于Igf2/H19基因座的印记表达至关重要。此后许多实验室的研究表明，CTCF有助于稳定细胞核中的长程相互作用。我们最近表明，在人类胰岛素基因座的情况下，这样一种跨越约300kb距离的相互作用可导致对一个靶基因的刺激，该靶基因本身对胰岛素分泌很重要。本文是名为：《时空染色质》的特刊的一部分。
