A type 2 diabetes-associated SNP in KCNQ1 (rs163184) modulates the binding activity of the locus for Sp3 and Lsd1/Kdm1a, potentially affecting CDKN1C expression.
A type 2 diabetes-associated SNP in KCNQ1 (rs163184) modulates the binding activity of the locus for Sp3 and Lsd1/Kdm1a, potentially affecting CDKN1C expression.
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DOI：
10.3892/ijmm.2017.3273
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发表时间：
2018-03
影响因子：
5.4
通讯作者：
Yasuda K
中科院分区：
文献类型：
--
作者：
Hiramoto M;Udagawa H;Ishibashi N;Takahashi E;Kaburagi Y;Miyazawa K;Funahashi N;Nammo T;Yasuda K
尽管全基因组关联研究表明钾电压门控通道亚家族 Q 成员 1 (KCNQ1) 是与 2 型糖尿病 (T2DM) 最显着相关的基因之一，但对疾病相关的单核苷酸多态性 (SNP) 进行功能注释仍然是一个挑战。最近，我们的小组描述了一种新的策略来识别以等位基因特异性方式与含有 SNP 的位点结合的蛋白质。本研究成功应用该策略来研究rs163184，这是一个位于KCNQ1内含子区域的T2DM易感性SNP。 DNA 结合蛋白的比较分析表明，包含 SNP rs163184 的基因组区域的结合活性在几种蛋白质（包括 Sp3 和 Lsd1/Kdm1a）的等位基因之间存在差异。 Sp3 优先与非风险 rs163184 等位基因结合，并刺激包含该区域的人工启动子的转录活性。 Lsd1/Kdm1a 被确定优先招募到 rs163184 区域的非风险等位基因，并降低人工启动子中 Sp3 依赖性转录活性。此外，在具有非风险等位基因的细胞中，SP3 敲低后，附近的细胞周期蛋白依赖性激酶抑制剂 1C (CDKN1C) 基因的表达上调。这表明 CDKN1C 可能是 SNP rs163184 的功能靶点之一，它调节 Sp3 和 Lsd1/Kdm1a 位点的结合活性。
Although genome-wide association studies have shown that potassium voltage-gated channel subfamily Q member 1 (KCNQ1) is one of the genes that is most significantly associated with type 2 diabetes mellitus (T2DM), functionally annotating disease-associated single nucleotide polymorphisms (SNPs) remains a challenge. Recently, our group described a novel strategy to identify proteins that bind to SNP-containing loci in an allele-specific manner. The present study successfully applied this strategy to investigate rs163184, a T2DM susceptibility SNP located in the intronic region of KCNQ1. Comparative analysis of DNA-binding proteins revealed that the binding activities for the genomic region containing SNP rs163184 differed between alleles for several proteins, including Sp3 and Lsd1/Kdm1a. Sp3 preferentially bound to the non-risk rs163184 allele and stimulated transcriptional activity in an artificial promoter containing this region. Lsd1/Kdm1a was identified to be preferentially recruited to the non-risk allele of the rs163184 region and reduced Sp3-dependent transcriptional activity in the artificial promoter. In addition, expression of the nearby cyclin-dependent kinase inhibitor 1C (CDKN1C) gene was revealed to be upregulated after SP3 knockdown in cells that possessed non-risk alleles. This suggests that CDKN1C is potentially one of the functional targets of SNP rs163184, which modulates the binding activity of the locus for Sp3 and Lsd1/Kdm1a.
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影响因子：
64.8
作者：
Sanyal, Amartya;Lajoie, Bryan R.;Jain, Gaurav;Dekker, Job
通讯作者：
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DOI：
10.1073/pnas.0601066103
发表时间：
2006-04-04
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作者：
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DOI：
10.1126/science.1222794
发表时间：
2012-09-07
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Maurano MT;Humbert R;Rynes E;Thurman RE;Haugen E;Wang H;Reynolds AP;Sandstrom R;Qu H;Brody J;Shafer A;Neri F;Lee K;Kutyavin T;Stehling-Sun S;Johnson AK;Canfield TK;Giste E;Diegel M;Bates D;Hansen RS;Neph S;Sabo PJ;Heimfeld S;Raubitschek A;Ziegler S;Cotsapas C;Sotoodehnia N;Glass I;Sunyaev SR;Kaul R;Stamatoyannopoulos JA
通讯作者：
Stamatoyannopoulos JA