DNA hypomethylation of a transcription factor binding site within the promoter of a gout risk gene NRBP1 upregulates its expression by inhibition of TFAP2A binding.
DNA hypomethylation of a transcription factor binding site within the promoter of a gout risk gene NRBP1 upregulates its expression by inhibition of TFAP2A binding.
复制标题
痛风风险基因 NRBP1 启动子内转录因子结合位点的 DNA 低甲基化通过抑制 TFAP2A 结合上调其表达
DOI：
10.1186/s13148-017-0401-z
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发表时间：
2017
影响因子：
5.7
通讯作者：
Zou H
中科院分区：
文献类型：
--
作者：
Zhu Z;Meng W;Liu P;Zhu X;Liu Y;Zou H
背景：全基因组关联研究（GWASs）已经确定了数十个与痛风相关的基因座，但对于大多数病例，导致这些关联的风险基因和潜在分子机制尚不清楚。本研究旨在了解一个常见的遗传变异，rs780093，在痛风的发展，在体外和在vivo.Results的分子机制：核受体结合蛋白1（NRBP1），作为痛风的风险基因，其调控区，72 bp的转录起始位点，指定为B1，通过整合分析全基因组基因型和DNA甲基化数据。我们观察到痛风患者外周血单核细胞（PBMCs）中NRBP1表达升高。体外荧光素酶报告基因和蛋白质下拉实验结果表明，DNA甲基化可以增加转录因子TFAP 2A与B1的结合，导致基因表达抑制。结论：NRBP1基因启动子区低甲基化降低了TFAP 2A的结合能力，从而导致NRBP1基因表达水平升高，这可能与痛风的发生发展有关。
Background:Genome-wide association studies (GWASs) have identified dozens of loci associated with gout, but for most cases, the risk genes and the underlying molecular mechanisms contributing to these associations are unknown. This study sought to understand the molecular mechanism of a common genetic variant, rs780093, in the development of gout, both in vitro and in vivo.Results:Nuclear receptor binding protein 1 (NRBP1), as a gout risk gene, and its regulatory region, 72 bp upstream of the transcription start site, designated as B1, were identified through integrative analyses of genome-wide genotype and DNA methylation data. We observed elevatedNRBP1expression in human peripheral blood mononuclear cells (PBMCs) from gout patients. In vitro luciferase reporter and protein pulldown assay results showed that DNA methylation could increase the binding of the transcription factor TFAP2A to B1, leading to suppressed gene expression. There results were further confirmed by in vivo bisulfite pyrosequencing showing that hypomethylation on B1 is associated with increasedNRBP1expression in gout patients.Conclusions:Hypomethylation at the promoter region ofNRBP1reduces the binding of TFAP2A and thus leads to elevatedNRBP1expression, which might contribute to the development of gout.
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影响因子：
4.9
作者：
Merriman TR
通讯作者：
Merriman TR
影响因子：
168.9
作者：
Dick, Katherine J.;Nelson, Christopher P.;Samani, Nilesh J.
通讯作者：
Samani, Nilesh J.
影响因子：
13.6
作者：
Kleber, Marcus E.;La Delgado, Gracie;Maerz, Winfried
通讯作者：
Maerz, Winfried
影响因子：
7.7
作者：
Hu S;Wan J;Su Y;Song Q;Zeng Y;Nguyen HN;Shin J;Cox E;Rho HS;Woodard C;Xia S;Liu S;Lyu H;Ming GL;Wade H;Song H;Qian J;Zhu H
通讯作者：
Zhu H
影响因子：
19.6
作者：
Hughes K;Flynn T;de Zoysa J;Dalbeth N;Merriman TR
通讯作者：
Merriman TR