Fat mass and obesity associated gene (FTO) expression is regulated negatively by the transcription factor Foxa2.
Fat mass and obesity associated gene (FTO) expression is regulated negatively by the transcription factor Foxa2.
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脂肪量和肥胖相关基因 (FTO) 表达受转录因子 Foxa2 负调节
DOI：
10.1371/journal.pone.0051082
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yang T
中科院分区：
文献类型：
--
作者：
Guo J;Ren W;Ding Y;Li A;Jia L;Su D;Liu X;Xu K;Yang T
脂肪质量与肥胖相关基因(FTO)是第一个与体重指数(BMI)和糖尿病风险相关的基因。FTO在大脑和胰腺中高度表达，参与调节饮食摄入和能量消耗。为了研究FTO表达的转录调控，我们创建了FTO启动子的5‘-缺失结构，以确定哪些转录因子与FTO表达最相关。荧光素酶活性分析证实在−201/+34处存在活化区。在转录起始点上游的100bp的β片段中发现了一个潜在的FOXA2(称为hnf-3−)结合位点和一个上游刺激因子结合位点。此外，通过突变，我们发现FOXA2结合序列(−26/−14)是人FTO启动子活性的负调控元件。USF结合部位不影响FTO启动子活性。染色质免疫沉淀(ChIP)实验证实Foxa2与FTO启动子结合。FOXA2在HEK 293细胞中的过表达显著下调FTO启动子的活性和表达。相反，siRNA抑制Foxa2可显著上调FTO的表达。这些发现表明，FOXA2负性调节人FTO基因的基础转录和表达。
Fat mass and obesity associated gene (FTO) is the first gene associated with body mass index (BMI) and risk for diabetes. FTO is highly expressed in the brain and pancreas, and is involved in regulating dietary intake and energy expenditure. To investigate the transcriptional regulation of FTO expression, we created 5′-deletion constructs of the FTO promoter to determine which transcription factors are most relevant to FTO expression. The presence of an activation region at −201/+34 was confirmed by luciferase activity analysis. A potential Foxa2 (called HNF-3β) binding site and an upstream stimulatory factor (USF)-binding site was identified in the −100 bp fragment upstream of the transcription start site (TSS). Furthermore, using mutagenesis, we identified the Foxa2 binding sequence (−26/−14) as a negative regulatory element to the activity of the human FTO promoter. The USF binding site did not affect the FTO promoter activity. Chromatin immunoprecipitation (ChIP) assays were performed to confirm Foxa2 binding to the FTO promoter. Overexpression of Foxa2 in HEK 293 cells significantly down-regulated FTO promoter activity and expression. Conversely, knockdown of Foxa2 by siRNA significantly up-regulated FTO expression. These findings suggest that Foxa2 negatively regulates the basal transcription and expression of the human FTO gene.
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影响因子：
--
作者：
Kaklamani V;Yi N;Sadim M;Siziopikou K;Zhang K;Xu Y;Tofilon S;Agarwal S;Pasche B;Mantzoros C
通讯作者：
Mantzoros C
影响因子：
7.7
作者：
Brennan, Paul;McKay, James;Smith, George Davey
通讯作者：
Smith, George Davey
影响因子：
3.7
作者：
Lurie G;Gaudet MM;Spurdle AB;Carney ME;Wilkens LR;Yang HP;Weiss NS;Webb PM;Thompson PJ;Terada K;Setiawan VW;Rebbeck TR;Prescott J;Orlow I;O'Mara T;Olson SH;Narod SA;Matsuno RK;Lissowska J;Liang X;Levine DA;Le Marchand L;Kolonel LN;Henderson BE;Garcia-Closas M;Doherty JA;De Vivo I;Chen C;Brinton LA;Akbari MR;Australian National Endometrial Cancer Study Group;Epidemiology of Endometrial Cancer Consortium (E2C2);Goodman MT
通讯作者：
Goodman MT
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
影响因子：
56.9
作者：
Frayling, Timothy M.;Timpson, Nicholas J.;McCarthy, Mark I.
通讯作者：
McCarthy, Mark I.