Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA

被引:646
作者
Wang, Dong [1 ]
Garcia-Bassets, Ivan [2 ,3 ]
Benner, Chris [1 ]
Li, Wenbo [2 ]
Su, Xue [2 ,4 ]
Zhou, Yiming [5 ]
Qiu, Jinsong [1 ]
Liu, Wen [2 ,4 ]
Kaikkonen, Minna U. [1 ]
Ohgi, Kenneth A. [2 ]
Glass, Christopher K. [1 ]
Rosenfeld, Michael G. [2 ]
Fu, Xiang-Dong [1 ]
机构
[1] Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Sch Med, Howard Hughes Med Inst, Dept Med, La Jolla, CA 92093 USA
[3] Univ Calif San Diego, Sch Med, Dept Med, Div Endocrinol & Metab, La Jolla, CA 92093 USA
[4] Univ Calif San Diego, Sch Med, Grad Program Biol, La Jolla, CA 92093 USA
[5] Digomics LLC, Malden, MA 02148 USA
关键词
FORKHEAD BOX A1; PROSTATE-CANCER; GENE-EXPRESSION; ANDROGEN RECEPTOR; HISTONE MODIFICATIONS; NUCLEAR RECEPTORS; HUMAN GENOME; IN-VIVO; CHROMATIN; SIGNATURES;
D O I
10.1038/nature10006
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell-type-specific gene expression programs(1-4), but how those enhancers are exploited to institute alternative, signal-dependent transcriptional responses remains poorly understood. Here we present evidence that cell-lineage-specific factors, such as FoxA1, can simultaneously facilitate and restrict key regulated transcription factors, exemplified by the androgen receptor (AR), to act on structurally and functionally distinct classes of enhancer. Consequently, FoxA1 downregulation, an unfavourable prognostic sign in certain advanced prostate tumours, triggers dramatic reprogramming of the hormonal response by causing a massive switch in AR binding to a distinct cohort of pre-established enhancers. These enhancers are functional, as evidenced by the production of enhancer-templated non-coding RNA (eRNA(5)) based on global nuclear run-on sequencing (GRO-seq) analysis(6), with a unique class apparently requiring no nucleosome remodelling to induce specific enhancer-promoter looping and gene activation. GRO-seq data also suggest that liganded AR induces both transcription initiation and elongation. Together, these findings reveal a large repository of active enhancers that can be dynamically tuned to elicit alternative gene expression programs, which may underlie many sequential gene expression events in development, cell differentiation and disease progression.
引用
收藏
页码:390 / +
页数:2
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