Germline deletion of Igh 3' regulatory region elements hs 5, 6, 7 (hs5-7) affects B cell-specific regulation, rearrangement, and insulation of the Igh locus.
Germline deletion of Igh 3' regulatory region elements hs 5, 6, 7 (hs5-7) affects B cell-specific regulation, rearrangement, and insulation of the Igh locus.
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DOI：
10.4049/jimmunol.1102763
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发表时间：
2012-03-15
期刊：
影响因子：
--
通讯作者：
Birshtein BK
中科院分区：
文献类型：
--
作者：
Volpi SA;Verma-Gaur J;Hassan R;Ju Z;Roa S;Chatterjee S;Werling U;Hou H Jr;Will B;Steidl U;Scharff M;Edelman W;Feeney AJ;Birshtein BK
位于Igh基因簇3′ ~28 kb区域内的调节元件（3′调节区，3′ RR）是类转换重组和浆细胞中高水平IgH表达所必需的。我们以前定义了新的DNase I超敏（HS）网站，即hs 5 -7，紧接该区域的下游。Hs 5 -7含有高密度的CTCF结合位点，CTCF是与哺乳动物绝缘子活性相关的锌指蛋白，并且是与DH区侧翼的CTCF位点相互作用的锚。为了测试hs 5 -7的功能，我们产生了包含所有三个hs元件的8 kb缺失的小鼠。来自hs 5 -7 KO小鼠的B细胞显示最近下游基因的表达适度增加。此外，与WT Igh等位基因相比，hs 5 -7 KO小鼠中的Igh等位基因处于较少收缩的构型，并且在近端VH 7183基因家族的使用中显示出2倍的增加。在B细胞发育、等位基因调控、类别转换重组和染色体成环方面，Hs 5 -7 KO小鼠与野生型小鼠基本上没有区别。我们得出结论，hs 5 -7--Igh基因座3′端的高密度CTCF结合区--影响远至500 kb的VH区的使用。
Regulatory elements located within a ~28 kb region 3′ of the Igh gene cluster (3′ regulatory region, 3′ RR) are required for class switch recombination and for high levels of IgH expression in plasma cells. We previously defined novel DNase I hypersensitive (hs) sites, i.e. hs5-7, immediately downstream of this region. Hs5-7 contains a high density of binding sites for CTCF, a zinc finger protein associated with mammalian insulator activity and is an anchor for interactions with CTCF sites flanking the DH region. To test the function of hs5-7, we have generated mice with an 8 kb deletion encompassing all three hs elements. B cells from hs5-7 KO mice showed a modest increase in expression of the nearest downstream gene. In addition, Igh alleles in hs5-7 KO mice were in a less contracted configuration compared to WT Igh alleles and showed a two-fold increase in the usage of proximal VH7183 gene families. Hs5-7 KO mice were essentially indistinguishable from wild type mice in B cell development, allelic regulation, class switch recombination, and chromosomal looping. We conclude that hs5-7--a high-density CTCF binding region at the 3′ end of the Igh locus--impacts usage of VH regions as far as 500 kb away.
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