17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells.
17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells.
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DOI：
10.1038/ncomms13426
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发表时间：
2016-11-16
影响因子：
16.6
通讯作者：
Vijayanand, Pandurangan
中科院分区：
文献类型：
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作者：
Schmiedel, Benjamin Joachim;Seumois, Gregory;Samaniego-Castruita, Daniela;Cayford, Justin;Schulten, Veronique;Chavez, Lukas;Ay, Ferhat;Sette, Alessandro;Peters, Bjoern;Vijayanand, Pandurangan
哮喘和自身免疫性疾病的易感性与改变ORMDL 3表达的17 q21单块遗传变异密切相关;然而，这些变异干扰基因表达的分子机制和这种影响最突出的细胞类型尚不清楚。我们发现几种17 q21变体重叠增强子主要存在于初级免疫细胞类型中。在携带哮喘风险等位基因的个体中，CD 4 + T细胞的ORMDL 3表达增加幅度最大（三倍），其中ORMDL 3负调节白细胞介素-2的产生。哮喘风险变异体rs 4065275和rs 12936231转换了17 q21位点的CTCF结合位点，4C-Seq分析显示，在CD 4 + T细胞中，几个位于被破坏的ZPBP 2 CTCF结合位点上游的远端顺式调节元件与ORMDL 3启动子区域相互作用，这些T细胞仅来自携带哮喘风险等位基因的受试者。总的来说，我们的研究结果表明，T细胞是受17 q21变体影响的最突出的细胞类型之一。 17 q21基因座的变异与哮喘易感性和其他自身免疫性疾病有关。在这里，作者对哮喘风险SNP进行了细胞类型特异性功能基因组分析，并显示了与免疫功能相关的差异基因调控的基因型特异性机制。
Asthma and autoimmune disease susceptibility has been strongly linked to genetic variants in the 17q21 haploblock that alter the expression of ORMDL3; however, the molecular mechanisms by which these variants perturb gene expression and the cell types in which this effect is most prominent are unclear. We found several 17q21 variants overlapped enhancers present mainly in primary immune cell types. CD4+ T cells showed the greatest increase (threefold) in ORMDL3 expression in individuals carrying the asthma-risk alleles, where ORMDL3 negatively regulated interleukin-2 production. The asthma-risk variants rs4065275 and rs12936231 switched CTCF-binding sites in the 17q21 locus, and 4C-Seq assays showed that several distal cis-regulatory elements upstream of the disrupted ZPBP2 CTCF-binding site interacted with the ORMDL3 promoter region in CD4+ T cells exclusively from subjects carrying asthma-risk alleles. Overall, our results suggested that T cells are one of the most prominent cell types affected by 17q21 variants. Variations in the 17q21 locus are linked to asthma susceptibility and other autoimmune diseases. Here, the authors perform cell type-specific functional genomic analyses of asthma-risk SNPs, and show a genotype specific mechanism of differential gene regulation relevant to immune function.
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影响因子：
5.2
作者：
Ferreira, Manuel A. R.;McRae, Allan F.;Martin, Nicholas G.
通讯作者：
Martin, Nicholas G.
影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
16.6
作者：
Ha, Sung Gil;Ge, Xiao Na;Bahaie, Nooshin S.;Kang, Bit Na;Rao, Amrita;Rao, Savita P.;Sriramarao, P.
通讯作者：
Sriramarao, P.
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
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