A tissue-specific chromatin loop activates the erythroid ankyrin-1 promoter
A tissue-specific chromatin loop activates the erythroid ankyrin-1 promoter
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DOI：
10.1182/blood-2012-08-450262
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发表时间：
2012-10-25
期刊：
影响因子：
20.3
通讯作者：
Bodine, David M.
中科院分区：
文献类型：
--
作者：
Yocum, Ashley O.;Steiner, Laurie A.;Bodine, David M.
人锚蛋白1基因（ANK 1）含有3个组织特异性的替代启动子。我们先前已经证明红系特异性锚蛋白1（ANK 1 E）核心启动子包含具有屏障绝缘子功能的5' DNase I超敏位点（HS），其防止体外和体内基因沉默。ANK 1 E屏障区的突变导致ANK 1 mRNA水平降低和遗传性球形红细胞增多症。在这份报告中，我们证明了第二ANK 1 E调控元件位于一个相邻的对DNA酶I HS位于5.6 kb的ANK 1 E启动子的3'在红细胞特异性DNA酶I敏感的染色质结构域的3'边界。3'调控元件在体外和转基因小鼠中表现出增强子活性，并且它具有与增强子元件相关的组蛋白修饰。ANK 1 E 3' HS之一含有增强子功能所需的NF-E2结合位点。我们发现，染色质环使3'增强子和NF-E2接近5'屏障区，包括ANK 1 E核心启动子。这些观察结果证明了替代启动子的组织特异性激活模型，该模型可能适用于类似30%具有表现出不同表达模式的替代启动子的哺乳动物基因。（血。2012;120（17）：3586-3593）
The human ankyrin-1 gene (ANK1) contains 3 tissue-specific alternative promoters. We have shown previously that the erythroid-specific ankyrin 1 (ANK1E) core promoter contains a 5' DNase I hypersensitive site (HS) with barrier insulator function that prevents gene silencing in vitro and in vivo. Mutations in the ANK1E barrier region lead to decreased ANK1 mRNA levels and hereditary spherocytosis. In this report, we demonstrate a second ANK1E regulatory element located in an adjacent pair of DNase I HS located 5.6 kb 3' of the ANK1E promoter at the 3' boundary of an erythroid-specific DNase I-sensitive chromatin domain. The 3' regulatory element exhibits enhancer activity in vitro and in transgenic mice, and it has the histone modifications associated with an enhancer element. One of the ANK1E 3' HS contains an NF-E2 binding site that is required for enhancer function. We show that a chromatin loop brings the 3' enhancer and NF-E2 into proximity with the 5' barrier region including the ANK1E core promoter. These observations demonstrate a model for the tissue-specific activation of alternative promoters that may be applicable to the similar to 30% of mammalian genes with alternative promoters that exhibit distinct expression patterns. (Blood. 2012;120(17):3586-3593)