Common variants in signaling transcription-factor-binding sites drive phenotypic variability in red blood cell traits.
Common variants in signaling transcription-factor-binding sites drive phenotypic variability in red blood cell traits.
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DOI：
10.1038/s41588-020-00738-2
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发表时间：
2020-12
期刊：
影响因子：
30.8
通讯作者：
Zon LI
中科院分区：
文献类型：
--
作者：
Choudhuri A;Trompouki E;Abraham BJ;Colli LM;Kock KH;Mallard W;Yang ML;Vinjamur DS;Ghamari A;Sporrij A;Hoi K;Hummel B;Boatman S;Chan V;Tseng S;Nandakumar SK;Yang S;Lichtig A;Superdock M;Grimes SN;Bowman TV;Zhou Y;Takahashi S;Joehanes R;Cantor AB;Bauer DE;Ganesh SK;Rinn J;Albert PS;Bulyk ML;Chanock SJ;Young RA;Zon LI
全基因组关联研究（GWAS）确定与人类性状和疾病相关的基因组变异。大多数性状相关变异位于细胞类型特异性增强子内，但对表型变异的分子机制了解较少。在这里，我们表明，许多增强子与红细胞（RBC）性状相关的变体映射到增强子，这些增强子由谱系特异性主转录因子（MTF）和信号传导转录因子（STFs）响应细胞外信号共同结合。大多数增强子变体位于STF而不是MTF基序上，干扰各种STF（BMP/TGFβ-定向SMAD或WNT-诱导的TCF）的DNA结合并影响靶基因表达。工程化的人血细胞和表达数量性状基因座（eQTL）分析证实，破坏的STF结合导致改变的基因表达。我们的研究结果表明，大多数的红细胞性状相关的变体，驻留在TF结合序列福尔斯落在STF靶序列，表明红细胞性状的表型变异可能源于改变细胞外刺激的反应。
Genome-wide association studies (GWAS) identify genomic variants associated with human traits and diseases. Most trait-associated variants are located within cell type-specific enhancers, but the molecular mechanisms governing phenotypic variation are less understood. Here, we show that many enhancer-variants associated with red blood cell (RBC) traits map to enhancers that are co-bound by lineage-specific master transcription factors (MTFs) and signaling transcription factors (STFs) responsive to extracellular signals. The majority of enhancer variants resides on STF and not MTF motifs, perturbing DNA-binding by various STFs (BMP/TGFβ-directed SMADs or WNT-induced TCFs) and affecting target gene expression. Engineered human blood cells and expression quantitative trait loci (eQTL) analyses verify that disrupted STF binding leads to altered gene expression. Our results propose that the majority of the RBC trait-associated variants that reside on TF binding sequences falls in STF target sequences, suggesting that the phenotypic variation of RBC traits could stem from altered responsiveness to extracellular stimuli.
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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
DOI：
10.1126/science.1162327
发表时间：
2009-06-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badis G;Berger MF;Philippakis AA;Talukder S;Gehrke AR;Jaeger SA;Chan ET;Metzler G;Vedenko A;Chen X;Kuznetsov H;Wang CF;Coburn D;Newburger DE;Morris Q;Hughes TR;Bulyk ML
通讯作者：
Bulyk ML
影响因子：
9.8
作者：
Gusev, Alexander;Lee, S. Hong;Price, Alkes L.
通讯作者：
Price, Alkes L.
影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M
影响因子：
20.3
作者：
Gregory, T;Yu, CN;Weiss, MJ
通讯作者：
Weiss, MJ