Obesity-associated variants within FTO form long-range functional connections with IRX3.
Obesity-associated variants within FTO form long-range functional connections with IRX3.
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DOI：
10.1038/nature13138
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发表时间：
2014-03-20
期刊：
影响因子：
64.8
通讯作者：
Nobrega, Marcelo A.
中科院分区：
文献类型：
--
作者：
Smemo, Scott;Tena, Juan J.;Kim, Kyoung-Han;Gamazon, Eric R.;Sakabe, Noboru J.;Gomez-Marin, Carlos;Aneas, Ivy;Credidio, Flavia L.;Sobreira, Debora R.;Wasserman, Nora F.;Lee, Ju Hee;Puviindran, Vijitha;Tam, Davis;Shen, Michael;Son, Joe Eun;Vakili, Niki Alizadeh;Sung, Hoon-Ki;Naranjo, Silvia;Acemel, Rafael D.;Manzanares, Miguel;Nagy, Andras;Cox, Nancy J.;Hui, Chi-Chung;Luis Gomez-Skarmeta, Jose;Nobrega, Marcelo A.
全基因组关联研究（GWAS）发现FTO内含子内的变异与肥胖和2型糖尿病（T2D）风险增加具有可重复性。虽然将这些非编码变异与肥胖联系起来的分子机制尚不明显，但随后的小鼠研究表明，FTO表达水平影响体重和组成表型。然而，肥胖相关变异与FTO表达或功能之间没有直接联系。在这里，我们发现FTO中与肥胖相关的非编码序列与同源盒基因IRX3在百万碱基距离上具有功能连接。肥胖相关的FTO区域直接与人类、小鼠和斑马鱼基因组中IRX3和FTO的启动子相互作用。此外，该区域内的远程增强子概括了IRX3表达的各个方面，这表明肥胖相关区间属于IRX3的调控范围。在人类大脑中，肥胖相关的snp与IRX3的表达有关，而与FTO无关。IRX3的表达与体重和组成的调节直接相关，IRX3缺陷小鼠的体重减少了25-30%，主要是通过脂肪量的减少和基础代谢率的增加以及白色脂肪组织的褐化。此外，Irx3显性阴性形式的下丘脑表达再现了Irx3缺陷小鼠的代谢表型。我们的数据假设IRX3是FTO中肥胖相关变异的功能性远程靶标，并且代表了身体质量和组成的新决定因素。
Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type-2 diabetes (T2D) . While the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes . Yet, no direct connection between the obesity-associated variants and FTO expression or function has been made . Here, we show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with the homeobox gene IRX3. The obesity-associated FTO region directly interacts with the promoters of IRX3 as well as FTO in the human, mouse, and zebrafish genomes. Furthermore, long-range enhancers within this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval belongs to the regulatory landscape of IRX3. Supporting this, obesity-associated SNPs are associated with expression of IRX3, but not FTO, in human brains. Directly linking IRX3 expression with regulation of body mass and composition, Irx3-deficient mice exhibit a 25–30% reduction in body weight, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Furthermore, hypothalamic expression of a dominant negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data posit that IRX3 is a functional long-range target of obesity-associated variants within FTO, and represents a novel determinant of body mass and composition.
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影响因子：
9.8
作者：
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通讯作者：
ENCODE Project Consortium
影响因子：
64.8
作者：
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影响因子：
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作者：
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通讯作者：
Christoffels, VM
DOI：
10.1126/science.1151710
发表时间：
2007-11-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gerken T;Girard CA;Tung YC;Webby CJ;Saudek V;Hewitson KS;Yeo GS;McDonough MA;Cunliffe S;McNeill LA;Galvanovskis J;Rorsman P;Robins P;Prieur X;Coll AP;Ma M;Jovanovic Z;Farooqi IS;Sedgwick B;Barroso I;Lindahl T;Ponting CP;Ashcroft FM;O'Rahilly S;Schofield CJ
通讯作者：
Schofield CJ