Genomic analyses of transcription factor binding, histone acetylation, and gene expression reveal mechanistically distinct classes of estrogen-regulated promoters

Kininis, M., Chen, B. S., Diehl, A. G., Isaacs, G. D., Zhang, T., Siepel, A. C., Clark, A. G., Kraus, W. L. (2007) Genomic analyses of transcription factor binding, histone acetylation, and gene expression reveal mechanistically distinct classes of estrogen-regulated promoters. Mol Cell Biol, 27 (14). pp. 5090-104. ISSN 0270-7306 (Print)0270-7306

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URL: http://www.ncbi.nlm.nih.gov/pubmed/17515612
DOI: 10.1128/mcb.00083-07

Abstract

To explore the global mechanisms of estrogen-regulated transcription, we used chromatin immunoprecipitation coupled with DNA microarrays to determine the localization of RNA polymerase II (Pol II), estrogen receptor alpha (ERalpha), steroid receptor coactivator proteins (SRC), and acetylated histones H3/H4 (AcH) at estrogen-regulated promoters in MCF-7 cells with or without estradiol (E2) treatment. In addition, we correlated factor occupancy with gene expression and the presence of transcription factor binding elements. Using this integrative approach, we defined a set of 58 direct E2 target genes based on E2-regulated Pol II occupancy and classified their promoters based on factor binding, histone modification, and transcriptional output. Many of these direct E2 target genes exhibit interesting modes of regulation and biological activities, some of which may be relevant to the onset and proliferation of breast cancers. Our studies indicate that about one-third of these direct E2 target genes contain promoter-proximal ERalpha-binding sites, which is considerably more than previous estimates. Some of these genes represent possible novel targets for regulation through the ERalpha/AP-1 tethering pathway. Our studies have also revealed several previously uncharacterized global features of E2-regulated gene expression, including strong positive correlations between Pol II occupancy and AcH levels, as well as between the E2-dependent recruitment of ERalpha and SRC at the promoters of E2-stimulated genes. Furthermore, our studies have revealed new mechanistic insights into E2-regulated gene expression, including the absence of SRC binding at E2-repressed genes and the presence of constitutively bound, promoter-proximally paused Pol IIs at some E2-regulated promoters. These mechanistic insights are likely to be relevant for understanding gene regulation by a wide variety of nuclear receptors.

Item Type: Paper
Uncontrolled Keywords: Acetylation/drug effects Base Sequence Cell Line, Tumor Chromatin Immunoprecipitation Enhancer Elements, Genetic/genetics Estradiol/*pharmacology Estrogen Receptor alpha/metabolism Gene Expression Regulation, Neoplastic/*drug effects Genes, Neoplasm Genome, Human/*genetics *Genomics Histones/*metabolism Humans Molecular Sequence Data Polymerase Chain Reaction Promoter Regions, Genetic/*genetics Protein Binding/drug effects RNA Polymerase II/metabolism Reproducibility of Results Sequence Analysis, DNA Transcription Factors/*metabolism
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > genomes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > histone
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:
Communities: CSHL labs > Siepel lab
Depositing User: Matt Covey
Date Deposited: 14 Jan 2015 20:31
Last Modified: 14 Jan 2015 20:31
PMCID: PMC1951957
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31074

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