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This version published online on March 4, 2004
Molecular Endocrinology, doi:10.1210/me.2003-0441
Molecular Endocrinology Vol. 0, No. 2004 200304411-
doi:10.1210/me.2003-0441
Copyright © 2004 by the Endocrine Society.
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Submitted on November 13, 2003
Accepted on February 26, 2004

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

Véronique Bourdeau, Julie Deschênes, Raphael 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, C.P. 6128 Succursale Centre-Ville, Montréal, Québec H3C 3J7, Canada; Departments of Physiology (V.B., J.H.W.), and Medicine (J.H.W., S.M.), McGill University, 3655 Drummond St, Montreal, Québec H3G 1Y6, Canada; McGill University and Genome Québec Innovation Centre (Y.N.), 740 Docteur Penfield Avenue, Montreal, Québec H3A 1A4, Canada; European Molecular Biology Laboratories (EMBL) (R.M.*, N.B., F.G.), Meyerhofstrasse, 1. D-69117, Heidelberg, Germany.

* To whom correspondence should be addressed. 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 ~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 non-conserved elements were also found, often in multiple occurrences, in over 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 ~10 kb from transcriptional start sites. Our results demonstrate that near-consensus EREs occur frequently in both genomes and that while chromatin structure likely modulates access to binding sites, far upstream elements can be evolutionarily conserved and bind ERs in vivo.
Key words: Estrogen receptor • estrogen response element • estrogen target gene • chromatin immunoprecipitation • genome-wide search

NURSA Molecule Pages Link:

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



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