Genetic variations of DNA bindings of FOXA1 and co-factors in breast cancer susceptibility.
Genetic variations of DNA bindings of FOXA1 and co-factors in breast cancer susceptibility.
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DOI：
10.1038/s41467-021-25670-9
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发表时间：
2021-09-13
影响因子：
16.6
通讯作者：
Guo X
中科院分区：
文献类型：
--
作者：
Wen W;Chen Z;Bao J;Long Q;Shu XO;Zheng W;Guo X
识别DNA结合被调节易感基因的遗传变异改变的转录因子（TFs）对于理解疾病病因中的转录失调是必要的。在这里，我们开发了一个统计框架来分析广泛的ChIP-seq和GWAS数据，并确定了22个乳腺癌风险相关的tf。我们发现，通过分析TF-DNA结合的遗传变异，FOXA1与辅助因子如ESR1和E2F1的相互作用，以及tf与染色质特征（即增强子）的相互作用在乳腺癌易感性中起着关键作用。利用22个tf占据的遗传变异，转录组全关联分析确定了52个以前未报道的乳腺癌易感基因，其中7个在乳腺相关细胞系的功能筛选中具有重要性。我们发现FOXA1和辅助因子形成了一个核心的tf转录网络，调控易感基因。我们的研究结果为乳腺癌易感性的TF-DNA结合（特别是FOXA1）的遗传变异提供了额外的见解。鉴定其结合位点受风险遗传变异影响的转录因子（TFs）仍然至关重要。在这里，作者开发了一个统计框架来分析ChIP-seq和GWAS数据，确定了22个乳腺癌风险相关的tf和FOXA1及其辅助因子的核心tf转录网络。
Identifying transcription factors (TFs) whose DNA bindings are altered by genetic variants that regulate susceptibility genes is imperative to understand transcriptional dysregulation in disease etiology. Here, we develop a statistical framework to analyze extensive ChIP-seq and GWAS data and identify 22 breast cancer risk-associated TFs. We find that, by analyzing genetic variations of TF-DNA bindings, the interaction of FOXA1 with co-factors such as ESR1 and E2F1, and the interaction of TFs with chromatin features (i.e., enhancers) play a key role in breast cancer susceptibility. Using genetic variants occupied by the 22 TFs, transcriptome-wide association analyses identify 52 previously unreported breast cancer susceptibility genes, including seven with evidence of essentiality from functional screens in breast relevant cell lines. We show that FOXA1 and co-factors form a core TF-transcriptional network regulating the susceptibility genes. Our findings provide additional insights into genetic variations of TF-DNA bindings (particularly for FOXA1) underlying breast cancer susceptibility. The identification of transcription factors (TFs) whose binding sites are affected by risk genetic variants remains crucial. Here, the authors develop a statistical framework to analyse ChIP-seq and GWAS data, identify 22 breast cancer risk-associated TFs and a core TF-transcriptional network for FOXA1 and co-factors.
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影响因子：
30.8
作者：
Dunning AM;Michailidou K;Kuchenbaecker KB;Thompson D;French JD;Beesley J;Healey CS;Kar S;Pooley KA;Lopez-Knowles E;Dicks E;Barrowdale D;Sinnott-Armstrong NA;Sallari RC;Hillman KM;Kaufmann S;Sivakumaran H;Moradi Marjaneh M;Lee JS;Hills M;Jarosz M;Drury S;Canisius S;Bolla MK;Dennis J;Wang Q;Hopper JL;Southey MC;Broeks A;Schmidt MK;Lophatananon A;Muir K;Beckmann MW;Fasching PA;Dos-Santos-Silva I;Peto J;Sawyer EJ;Tomlinson I;Burwinkel B;Marme F;Guénel P;Truong T;Bojesen SE;Flyger H;González-Neira A;Perez JI;Anton-Culver H;Eunjung L;Arndt V;Brenner H;Meindl A;Schmutzler RK;Brauch H;Hamann U;Aittomäki K;Blomqvist C;Ito H;Matsuo K;Bogdanova N;Dörk T;Lindblom A;Margolin S;Kosma VM;Mannermaa A;Tseng CC;Wu AH;Lambrechts D;Wildiers H;Chang-Claude J;Rudolph A;Peterlongo P;Radice P;Olson JE;Giles GG;Milne RL;Haiman CA;Henderson BE;Goldberg MS;Teo SH;Yip CH;Nord S;Borresen-Dale AL;Kristensen V;Long J;Zheng W;Pylkäs K;Winqvist R;Andrulis IL;Knight JA;Devilee P;Seynaeve C;Figueroa J;Sherman ME;Czene K;Darabi H;Hollestelle A;van den Ouweland AM;Humphreys K;Gao YT;Shu XO;Cox A;Cross SS;Blot W;Cai Q;Ghoussaini M;Perkins BJ;Shah M;Choi JY;Kang D;Lee SC;Hartman M;Kabisch M;Torres D;Jakubowska A;Lubinski J;Brennan P;Sangrajrang S;Ambrosone CB;Toland AE;Shen CY;Wu PE;Orr N;Swerdlow A;McGuffog L;Healey S;Lee A;Kapuscinski M;John EM;Terry MB;Daly MB;Goldgar DE;Buys SS;Janavicius R;Tihomirova L;Tung N;Dorfling CM;van Rensburg EJ;Neuhausen SL;Ejlertsen B;Hansen TV;Osorio A;Benitez J;Rando R;Weitzel JN;Bonanni B;Peissel B;Manoukian S;Papi L;Ottini L;Konstantopoulou I;Apostolou P;Garber J;Rashid MU;Frost D;EMBRACE;Izatt L;Ellis S;Godwin AK;Arnold N;Niederacher D;Rhiem K;Bogdanova-Markov N;Sagne C;Stoppa-Lyonnet D;Damiola F;GEMO Study Collaborators;Sinilnikova OM;Mazoyer S;Isaacs C;Claes KB;De Leeneer K;de la Hoya M;Caldes T;Nevanlinna H;Khan S;Mensenkamp AR;HEBON;Hooning MJ;Rookus MA;Kwong A;Olah E;Diez O;Brunet J;Pujana MA;Gronwald J;Huzarski T;Barkardottir RB;Laframboise R;Soucy P;Montagna M;Agata S;Teixeira MR;kConFab Investigators;Park SK;Lindor N;Couch FJ;Tischkowitz M;Foretova L;Vijai J;Offit K;Singer CF;Rappaport C;Phelan CM;Greene MH;Mai PL;Rennert G;Imyanitov EN;Hulick PJ;Phillips KA;Piedmonte M;Mulligan AM;Glendon G;Bojesen A;Thomassen M;Caligo MA;Yoon SY;Friedman E;Laitman Y;Borg A;von Wachenfeldt A;Ehrencrona H;Rantala J;Olopade OI;Ganz PA;Nussbaum RL;Gayther SA;Nathanson KL;Domchek SM;Arun BK;Mitchell G;Karlan BY;Lester J;Maskarinec G;Woolcott C;Scott C;Stone J;Apicella C;Tamimi R;Luben R;Khaw KT;Helland Å;Haakensen V;Dowsett M;Pharoah PD;Simard J;Hall P;García-Closas M;Vachon C;Chenevix-Trench G;Antoniou AC;Easton DF;Edwards SL
通讯作者：
Edwards SL
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
7.3
作者：
Kawahara, Brian;Moller, Travis;Mascharak, Pradip K.
通讯作者：
Mascharak, Pradip K.
DOI：
10.1158/1055-9965.epi-15-0363
发表时间：
2015-11
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Guo X;Long J;Zeng C;Michailidou K;Ghoussaini M;Bolla MK;Wang Q;Milne RL;Shu XO;Cai Q;Beesley J;Kar SP;Andrulis IL;Anton-Culver H;Arndt V;Beckmann MW;Beeghly-Fadiel A;Benitez J;Blot W;Bogdanova N;Bojesen SE;Brauch H;Brenner H;Brinton L;Broeks A;Brüning T;Burwinkel B;Cai H;Canisius S;Chang-Claude J;Choi JY;Couch FJ;Cox A;Cross SS;Czene K;Darabi H;Devilee P;Droit A;Dörk T;Fasching PA;Fletcher O;Flyger H;Fostira F;Gaborieau V;García-Closas M;Giles GG;Grip M;Guénel P;Haiman CA;Hamann U;Hartman M;Hollestelle A;Hopper JL;Hsiung CN;Ito H;Jakubowska A;Johnson N;Kabisch M;Kang D;Khan S;Knight JA;Kosma VM;Lambrechts D;Le Marchand L;Li J;Lindblom A;Lophatananon A;Lubinski J;Mannermaa A;Manoukian S;Margolin S;Marme F;Matsuo K;McLean CA;Meindl A;Muir K;Neuhausen SL;Nevanlinna H;Nord S;Olson JE;Orr N;Peterlongo P;Putti TC;Rudolph A;Sangrajrang S;Sawyer EJ;Schmidt MK;Schmutzler RK;Shen CY;Shi J;Shrubsole MJ;Southey MC;Swerdlow A;Teo SH;Thienpont B;Toland AE;Tollenaar RA;Tomlinson IP;Truong T;Tseng CC;van den Ouweland A;Wen W;Winqvist R;Wu A;Yip CH;Zamora MP;Zheng Y;Hall P;Pharoah PD;Simard J;Chenevix-Trench G;kConFab Investigators;Dunning AM;Easton DF;Zheng W
通讯作者：
Zheng W
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK