Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA

Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell-type-specific gene expression programs, but how those enhancers are exploited to institute alternative, signal-dependent transcriptional responses remains poorly understood. Here we present evidence tha...

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Bibliographic Details
Published in:Nature (London) 2011-06, Vol.474 (7351), p.390-394
Main Authors: DONG WANG, GARCIA-BASSETS, Ivan, GLASS, Christopher K, ROSENFELD, Michael G, FU, Xiang-Dong, BENNER, Chris, WENBO LI, XUE SU, YIMING ZHOU, JINSONG QIU, WEN LIU, KAIKKONEN, Minna U, OHGI, Kenneth A
Format: Article
Language:English
Subjects:
Base Sequence
Binding sites
Biological and medical sciences
Cell Line, Tumor
Cell Lineage
Development and progression
Dihydrotestosterone - pharmacology
Down-Regulation
Enhancer Elements, Genetic - genetics
Fundamental and applied biological sciences. Psychology
Gene expression
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Genetic aspects
Genome, Human - genetics
Health aspects
HEK293 Cells
Hepatocyte Nuclear Factor 3-alpha - deficiency
Hepatocyte Nuclear Factor 3-alpha - genetics
Hepatocyte Nuclear Factor 3-alpha - metabolism
Histones - metabolism
Humans
Kallikreins
Male
Molecular and cellular biology
Molecular genetics
Prostate cancer
Prostate-Specific Antigen
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Proteins
Receptors, Androgen - metabolism
RNA
RNA, Small Interfering - genetics
RNA, Small Interfering - metabolism
RNA, Untranslated - genetics
Structure
Transcription (Genetics)
Transcription factors
Transcription, Genetic - genetics
Transcription. Transcription factor. Splicing. Rna processing
Tumors
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Items that cite this one
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Description
Summary:Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell-type-specific gene expression programs, 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) based on global nuclear run-on sequencing (GRO-seq) analysis, 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.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature10006