Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma.
Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma.
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主转录因子在食管腺癌中形成互连电路并协调转录网络。
DOI：
10.1136/gutjnl-2019-318325
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发表时间：
2020-04
期刊：
影响因子：
24.5
通讯作者：
Koeffler HP
中科院分区：
文献类型：
--
作者：
Chen L;Huang M;Plummer J;Pan J;Jiang YY;Yang Q;Silva TC;Gull N;Chen S;Ding LW;An O;Yang H;Cheng Y;Said JW;Doan N;Dinjens WN;Waters KM;Tuli R;Gayther SA;Klempner SJ;Berman BP;Meltzer SJ;Lin DC;Koeffler HP
虽然食管鳞状细胞癌（ESCC）在西方人群中仍然不常见，但食管腺癌（EAC）的发病率在过去40年中增加了6至8倍。我们的目的是表征食管癌和亚型特异性基因调控模式及其上游转录因子（TF）。为了确定调控元件，我们用染色质免疫沉淀测序（ChIP-Seq）分析了新鲜冷冻的食管正常样本、肿瘤和细胞系。进行数学建模以建立由主TF形成的（超级）增强子景观和相互连接的转录电路。通过ChIP-Seq、4C-Seq和荧光素酶测定研究主TF之间的共调节和协作。在体外和体内评价候选因子的生物学功能。我们发现在食管癌的两种亚型中（超级）增强子库的广泛和普遍的改变，导致无数新的癌基因和信号传导途径的转录激活，其中一些可能被利用（例如，LIF途径）。针对EAC，我们从生物信息学角度重建并功能验证了由ELF 3、KLF 5、GATA 6和EHF 4个主转录因子组成的相互连接的回路，它们通过与每个超级增强子相互作用来促进彼此的表达。在下游，这些主TF占据了几乎所有的EAC超级增强子并协同协调EAC转录组。转录回路中的每个TF在EAC中高度特异性表达，并在功能上促进EAC细胞增殖和存活。通过建立EAC表观基因组的癌症和亚型特异性特征，我们的研究结果有望改变对EAC转录失调和成瘾的理解，同时为开发针对这种恶性肿瘤的新型治疗方式提供分子线索。
While esophageal squamous cell carcinoma (ESCC) remains infrequent in Western populations, the incidence of esophageal adenocarcinoma (EAC) has increased 6- to 8-fold over the past 4 decades. We aimed to characterize esophageal cancer- and subtypes-specific gene regulation patterns and their upstream transcription factors (TFs). To identify regulatory elements, we profiled fresh-frozen esophageal normal samples, tumors and cell lines with chromatin immunoprecipitation sequencing (ChIP-Seq). Mathematical modeling was performed to establish (super)-enhancers landscapes and inter-connected transcriptional circuitry formed by master TFs. Co-regulation and cooperation between master TFs were investigated by ChIP-Seq, 4C-Seq and luciferase assay. Biological functions of candidate factors were evaluated both in vitro and in vivo. We found widespread and pervasive alterations of the (super)-enhancer reservoir in both subtypes of esophageal cancer, leading to transcriptional activation of a myriad of novel oncogenes and signaling pathways, some of which may be exploited pharmacologically (e.g., LIF pathway). Focusing on EAC, we bioinformatically reconstructed and functionally validated an interconnected circuitry formed by 4 master TFs: ELF3, KLF5, GATA6 and EHF, which promoted each others’ expression by interacting with each super-enhancer. Downstream, these master TFs occupied almost all EAC super-enhancers and cooperatively orchestrated EAC transcriptome. Each TF within the transcriptional circuitry was highly and specifically expressed in EAC and functionally promoted EAC cell proliferation and survival. By establishing cancer- and subtype-specific features of EAC epigenome, our findings promise to transform understanding of the transcriptional dysregulation and addiction of EAC, while providing molecular clues to develop novel therapeutic modalities against this malignancy.
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影响因子：
64.8
作者：
Cancer Genome Atlas Research Network;Analysis Working Group: Asan University;BC Cancer Agency;Brigham and Women’s Hospital;Broad Institute;Brown University;Case Western Reserve University;Dana-Farber Cancer Institute;Duke University;Greater Poland Cancer Centre;Harvard Medical School;Institute for Systems Biology;KU Leuven;Mayo Clinic;Memorial Sloan Kettering Cancer Center;National Cancer Institute;Nationwide Children’s Hospital;Stanford University;University of Alabama;University of Michigan;University of North Carolina;University of Pittsburgh;University of Rochester;University of Southern California;University of Texas MD Anderson Cancer Center;University of Washington;Van Andel Research Institute;Vanderbilt University;Washington University;Genome Sequencing Center: Broad Institute;Washington University in St. Louis;Genome Characterization Centers: BC Cancer Agency;Broad Institute;Harvard Medical School;Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University;University of North Carolina;University of Southern California Epigenome Center;University of Texas MD Anderson Cancer Center;Van Andel Research Institute;Genome Data Analysis Centers: Broad Institute;Brown University:;Harvard Medical School;Institute for Systems Biology;Memorial Sloan Kettering Cancer Center;University of California Santa Cruz;University of Texas MD Anderson Cancer Center;Biospecimen Core Resource: International Genomics Consortium;Research Institute at Nationwide Children’s Hospital;Tissue Source Sites: Analytic Biologic Services;Asan Medical Center;Asterand Bioscience;Barretos Cancer Hospital;BioreclamationIVT;Botkin Municipal Clinic;Chonnam National University Medical School;Christiana Care Health System;Cureline;Duke University;Emory University;Erasmus University;Indiana University School of Medicine;Institute of Oncology of Moldova;International Genomics Consortium;Invidumed;Israelitisches Krankenhaus Hamburg;Keimyung University School of Medicine;Memorial Sloan Kettering Cancer Center;National Cancer Center Goyang;Ontario Tumour Bank;Peter MacCallum Cancer Centre;Pusan National University Medical School;Ribeirão Preto Medical School;St. Joseph’s Hospital &Medical Center;St. Petersburg Academic University;Tayside Tissue Bank;University of Dundee;University of Kansas Medical Center;University of Michigan;University of North Carolina at Chapel Hill;University of Pittsburgh School of Medicine;University of Texas MD Anderson Cancer Center;Disease Working Group: Duke University;Memorial Sloan Kettering Cancer Center;National Cancer Institute;University of Texas MD Anderson Cancer Center;Yonsei University College of Medicine;Data Coordination Center: CSRA Inc.;Project Team: National Institutes of Health
通讯作者：
Project Team: National Institutes of Health
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
4.6
作者：
Cheng, Zhongping;Guo, Jing;Qu, Xiaoyan
通讯作者：
Qu, Xiaoyan
影响因子：
24.5
作者：
Chia, Na-Yu;Deng, Niantao;Tan, Patrick
通讯作者：
Tan, Patrick
影响因子：
30.8
作者：
Dulak, Austin M.;Stojanov, Petar;Peng, Shouyong;Lawrence, Michael S.;Fox, Cameron;Stewart, Chip;Bandla, Santhoshi;Imamura, Yu;Schumacher, Steven E.;Shefler, Erica;McKenna, Aaron;Carter, Scott L.;Cibulskis, Kristian;Sivachenko, Andrey;Saksena, Gordon;Voet, Douglas;Ramos, Alex H.;Auclair, Daniel;Thompson, Kristin;Sougnez, Carrie;Onofrio, Robert C.;Guiducci, Candace;Beroukhim, Rameen;Zhou, Zhongren;Lin, Lin;Lin, Jules;Reddy, Rishindra;Chang, Andrew;Landrenau, Rodney;Pennathur, Arjun;Ogino, Shuji;Luketich, James D.;Golub, Todd R.;Gabriel, Stacey B.;Lander, Eric S.;Beer, David G.;Godfrey, Tony E.;Getz, Gad;Bass, Adam J.
通讯作者：
Bass, Adam J.