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Molecular Endocrinology, doi:10.1210/me.2003-0441
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Molecular Endocrinology 18 (6): 1411-1427
Copyright © 2004 by The Endocrine Society

Genome-Wide Identification of High-Affinity Estrogen Response Elements in Human and Mouse

Véronique Bourdeau, Julie Deschênes, Raphaël Métivier, Yoshihiko Nagai, Denis Nguyen, Nancy Bretschneider, Frank Gannon, John H. White and Sylvie Mader

Département de Biochimie (V.B., J.D., D.N., S.M.), Université de Montréal, Montréal, Québec, Canada H3C 3J7; Departments of Physiology (V.B., J.H.W.), and Medicine (J.H.W., S.M.), McGill University, Montréal, Québec, Canada H3G 1Y6; McGill University and Genome Québec Innovation Centre (Y.N.), Montréal, Québec, Canada H3A 1A4; and European Molecular Biology Laboratories (R.M., N.B., F.G.), D-69117 Heidelberg, Germany

Address all correspondence and requests for reprints to: Sylvie Mader, Département de Biochimie, Université de Montréal, CP 6128 Succursale Centre-Ville, Montréal, Québec, Canada H3C 3J7. E-mail: sylvie.mader{at}umontreal.ca.

Although estrogen receptors (ERs) recognize 15-bp palindromic estrogen response elements (EREs) with maximal affinity in vitro, few near-consensus sequences have been characterized in estrogen target genes. Here we report the design of a genome-wide screen for high-affinity EREs and the identification of approximately 70,000 motifs in the human and mouse genomes. EREs are enriched in regions proximal to the transcriptional start sites, and approximately 1% of elements appear conserved in the flanking regions (–10 kb to +5 kb) of orthologous human and mouse genes. Conserved and nonconserved elements were also found, often in multiple occurrences, in more than 230 estrogen-stimulated human genes previously identified from expression studies. In genes containing known EREs, we also identified additional distal elements, sometimes with higher in vitro binding affinity and/or better conservation between the species considered. Chromatin immunoprecipitation experiments in breast cancer cell lines indicate that most novel elements present in responsive genes bind ER{alpha} in vivo, including some EREs located up to approximately 10 kb from transcriptional start sites. Our results demonstrate that near-consensus EREs occur frequently in both genomes and that whereas chromatin structure likely modulates access to binding sites, far upstream elements can be evolutionarily conserved and bind ERs in vivo.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ
Ligands:   17β-Estradiol



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