Enhancer transcription reveals subtype-specific gene expression programs controlling breast cancer pathogenesis.
Enhancer transcription reveals subtype-specific gene expression programs controlling breast cancer pathogenesis.
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DOI：
10.1101/gr.226019.117
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发表时间：
2018-03
期刊：
影响因子：
7
通讯作者：
Kraus WL
中科院分区：
文献类型：
--
作者：
Franco HL;Nagari A;Malladi VS;Li W;Xi Y;Richardson D;Allton KL;Tanaka K;Li J;Murakami S;Keyomarsi K;Bedford MT;Shi X;Li W;Barton MC;Dent SYR;Kraus WL
非编码转录是活性增强子的一个重要特征，它将转录因子(TF)与控制基因表达的分子机制联系起来。为了确定乳腺癌增强子活性与生物学结果之间的关系，我们分析了11个不同的人类乳腺癌细胞系的转录(使用Gro-seq和RNA-seq)和表观基因组(使用芯片-seq)，这些细胞系代表乳腺癌的五个主要分子亚型，以及两个永生化(“正常”)的人乳腺细胞系。此外，我们开发了一种稳健和无偏见的计算管道，通过整合增强子转录的大小、TF mRNA表达水平、TF基序P值以及H3K4me1和H3K27ac的浓缩，同时识别可能的亚型特异性增强子及其同源TF。当应用于上述13种不同的细胞系时，增强子元件总功能评分(TFSEE)确定了关键的乳腺癌亚型特异性转录因子，它们作用于转录增强子，决定基因表达模式，决定生长结果，包括叉头因子、FOSL1和PLAG1。FOSL1是一个Fos家族的转录因子，(1)在三重阴性乳腺癌(TNBC)细胞的增强剂中高度富含，(2)是TNBC细胞增殖和活性的关键调节因子，而不是Lumina A细胞，(3)与TNBC乳腺癌患者的不良预后有关。综上所述，我们的结果验证了我们的增强子识别管道，并揭示了在乳腺癌细胞中转录的增强子直接领导促进发病的关键基因调控网络。
Noncoding transcription is a defining feature of active enhancers, linking transcription factor (TF) binding to the molecular mechanisms controlling gene expression. To determine the relationship between enhancer activity and biological outcomes in breast cancers, we profiled the transcriptomes (using GRO-seq and RNA-seq) and epigenomes (using ChIP-seq) of 11 different human breast cancer cell lines representing five major molecular subtypes of breast cancer, as well as two immortalized (“normal”) human breast cell lines. In addition, we developed a robust and unbiased computational pipeline that simultaneously identifies putative subtype-specific enhancers and their cognate TFs by integrating the magnitude of enhancer transcription, TF mRNA expression levels, TF motif P-values, and enrichment of H3K4me1 and H3K27ac. When applied across the 13 different cell lines noted above, the Total Functional Score of Enhancer Elements (TFSEE) identified key breast cancer subtype-specific TFs that act at transcribed enhancers to dictate gene expression patterns determining growth outcomes, including Forkhead TFs, FOSL1, and PLAG1. FOSL1, a Fos family TF, (1) is highly enriched at the enhancers of triple negative breast cancer (TNBC) cells, (2) acts as a key regulator of the proliferation and viability of TNBC cells, but not Luminal A cells, and (3) is associated with a poor prognosis in TNBC breast cancer patients. Taken together, our results validate our enhancer identification pipeline and reveal that enhancers transcribed in breast cancer cells direct critical gene regulatory networks that promote pathogenesis.
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影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
DOI：
10.1038/nrm3949
发表时间：
2015-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Heinz S;Romanoski CE;Benner C;Glass CK
通讯作者：
Glass CK
影响因子：
64.5
作者：
Hah N;Danko CG;Core L;Waterfall JJ;Siepel A;Lis JT;Kraus WL
通讯作者：
Kraus WL
模因套件：用于发现和搜索的工具。
影响因子：
14.9
作者：
Bailey TL;Boden M;Buske FA;Frith M;Grant CE;Clementi L;Ren J;Li WW;Noble WS
通讯作者：
Noble WS
影响因子：
64.5
作者：
Ciriello G;Gatza ML;Beck AH;Wilkerson MD;Rhie SK;Pastore A;Zhang H;McLellan M;Yau C;Kandoth C;Bowlby R;Shen H;Hayat S;Fieldhouse R;Lester SC;Tse GM;Factor RE;Collins LC;Allison KH;Chen YY;Jensen K;Johnson NB;Oesterreich S;Mills GB;Cherniack AD;Robertson G;Benz C;Sander C;Laird PW;Hoadley KA;King TA;TCGA Research Network;Perou CM
通讯作者：
Perou CM