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Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA

Nature volume 474, pages 390–394 (2011)Cite this article

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Abstract

Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell-type-specific gene expression programs1,2,3,4, 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 (eRNA5) based on global nuclear run-on sequencing (GRO-seq) analysis6, 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.

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Figure 1: FoxA1 contributes to the enhancer code in prostate cancer cells.
Figure 2: AR reprogramming and induced alternative hormonal response.
Figure 3: Transcriptional response on individual enhancer programs to FOXA1 downregulation.
Figure 4: Distinct classes of AR enhancers in the human genome.

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Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

High-throughput data are deposited in Gene ExpressionOmnibus under accession number GSE27823 for all ChIP-seq and GRO-seq experiments and GSE27682 for microarray data.

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Acknowledgements

We are grateful to H.-J. Kung for providing the PC3-AR cell lines, C. Sawyers for providing the LNCaP-AR cell line, and J. Hightower, D. Benson and M. Fisher for assistance with figure and manuscript preparation. This work was supported by grants from US Army Medical Research and Material Command (grant W81XWH-05-1-0100) to I.G.-B., the National Institutes of Health (DK01847, DK37949, DK074868, NS34934), Department of Defense and the National Cancer Institute (CA97134) to M.G.R.; the National Institutes of Health (GM049369 and HG004659) to X.-D.F.; and the Prostate Cancer Foundation to M.G.R. and X.-D.F. M.G.R. is an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

  1. Dong Wang, Ivan Garcia-Bassets and Chris Benner: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA,

    Dong Wang, Chris Benner, Jinsong Qiu, Minna U. Kaikkonen, Christopher K. Glass & Xiang-Dong Fu

  2. Department of Medicine, Howard Hughes Medical Institute, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA,

    Ivan Garcia-Bassets, Wenbo Li, Xue Su, Wen Liu, Kenneth A. Ohgi & Michael G. Rosenfeld

  3. Department of Medicine, Division of Endocrinology and Metabolism, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA,

    Ivan Garcia-Bassets

  4. Graduate Program in Biology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA,

    Xue Su & Wen Liu

  5. Digomics LLC, PO Box 30, Malden, Massachusetts 02148, USA,

    Yiming Zhou

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Contributions

D.W., I.G.-B., M.G.R. and X.-D.F. designed the experiments; D.W. and I.G.B. performed most of them. C.B. performed all computational analyses. W.L. and M.K. performed GRO-seq; X.S. performed the 3C assay; Y.Z. analysed human samples; and J.Q. performed proliferation assays. K.A.O. and W.L. generated AR constructs. I.G.-B., D.W., M.G.R. and X.-D.F. wrote the manuscript with contributions from C.B. and C.K.G.

Corresponding authors

Correspondence to Ivan Garcia-Bassets, Michael G. Rosenfeld or Xiang-Dong Fu.

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The authors declare no competing financial interests.

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Wang, D., Garcia-Bassets, I., Benner, C. et al. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474, 390–394 (2011). https://doi.org/10.1038/nature10006

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