Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 30, Issue 16, Pages 3943-3955Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00118-10
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Funding
- NIH [5R01 CA18119, P01 AG 024387, T32 HD07028, T32 CA009523, R01 CA52599, R01 DK 058110]
- Breast Cancer Research Foundation
- Singapore Agency for Science, Technology and Research
- [P30 DK063491]
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Nuclear receptor estrogen receptor alpha (ER alpha) controls the expression of hundreds of genes responsible for target cell phenotypic properties, but the relative importance of direct versus tethering mechanisms of DNA binding has not been established. In this first report, we examine the genome-wide chromatin localization of an altered-specificity mutant ER with a DNA binding domain deficient in binding to estrogen response element (ERE)-containing DNA (DBDmut ER) versus wild-type ER alpha. Using high-throughput sequencing of ER chromatin immunoprecipitations (ChIP-Seq) and mRNA transcriptional profiling, we show that direct ERE binding is required for most of (75%) estrogen-dependent gene regulation and 90% of hormone-dependent recruitment of ER to genomic binding sites. De novo motif analysis of the chromatin binding regions in MDA-MB-231 human breast cancer cells defined unique transcription factor profiles responsible for genes regulated through tethering versus direct ERE binding, with Runx motifs enriched in ER-tethered sites. We confirmed a role for Runx1 in mediating ER alpha genomic recruitment and regulation of tethering genes. Our findings delineate the contributions of direct receptor ERE binding versus binding through response elements for other transcription factors in chromatin localization and ER-dependent gene regulation, paradigms likely to underlie the gene regulatory actions of other nuclear receptors as well.
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