Genome-wide analysis of estrogen receptor α DNA binding and tethering mechanisms identifies Runx1 as a novel tethering factor in receptor-mediated transcriptional activation

Joshua D. Stender, Kyuri Kim, Tze Howe Charn, Barry Komm, Ken C.N. Chang, W. Lee Kraus, Christopher Benner, Christopher K. Glass, Benita S. Katzenellenbogen

Research output: Contribution to journalArticle

Abstract

Nuclear receptor estrogen receptor alpha (ERα) 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 ERα. 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 ERα 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.

Original languageEnglish (US)
Pages (from-to)3943-3955
Number of pages13
JournalMolecular and cellular biology
Volume30
Issue number16
DOIs
StatePublished - Aug 1 2010

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Estrogen Receptor alpha
Estrogen Receptors
Transcriptional Activation
Genome
Response Elements
DNA
Estrogens
Chromatin
Cytoplasmic and Nuclear Receptors
Genes
Transcription Factors
Chromatin Immunoprecipitation
Regulator Genes
Binding Sites
Hormones
Breast Neoplasms
Gene Expression
Messenger RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Genome-wide analysis of estrogen receptor α DNA binding and tethering mechanisms identifies Runx1 as a novel tethering factor in receptor-mediated transcriptional activation. / Stender, Joshua D.; Kim, Kyuri; Charn, Tze Howe; Komm, Barry; Chang, Ken C.N.; Kraus, W. Lee; Benner, Christopher; Glass, Christopher K.; Katzenellenbogen, Benita S.

In: Molecular and cellular biology, Vol. 30, No. 16, 01.08.2010, p. 3943-3955.

Research output: Contribution to journalArticle

Stender, Joshua D. ; Kim, Kyuri ; Charn, Tze Howe ; Komm, Barry ; Chang, Ken C.N. ; Kraus, W. Lee ; Benner, Christopher ; Glass, Christopher K. ; Katzenellenbogen, Benita S. / Genome-wide analysis of estrogen receptor α DNA binding and tethering mechanisms identifies Runx1 as a novel tethering factor in receptor-mediated transcriptional activation. In: Molecular and cellular biology. 2010 ; Vol. 30, No. 16. pp. 3943-3955.
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