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Differential Regulation of Native Estrogen Receptor-Regulatory Elements by Estradiol, Tamoxifen, and Raloxifene

Departments of Obstetrics, Gynecology, and Reproductive Sciences and Center for Reproductive Sciences, Cellular and Molecular Pharmacology (N.L., D.T., C.B.H., L.J.B., J.S., D.C.L), University of California, San Francisco, California 94143; Departments of Nutritional Sciences and Toxicology (D.C.L.) and Statistics (X.Z., H.T., T.P.S.), University of California, Berkeley, California 94720; and Division of Genetics and Bioinformatics, The Walter and Eliza Hall Institute of Medical Research (T.S., T.P.S.), Parkville, Victoria 3052, Australia

Address all correspondence and requests for reprints to: D.C.L: University of California, San Francisco, MS 1258 P.O. Box 0556, San Francisco, California 94143-0556. E-mail: dale{at}leitmanlab.com.

Estrogen receptors (ERs) regulate gene transcription by interacting with regulatory elements. Most information regarding how ER activates genes has come from studies using a small set of target genes or simple consensus sequences such as estrogen response element, activator protein 1, and Sp1 elements. However, these elements cannot explain the differences in gene regulation patterns and clinical effects observed with estradiol (E₂) and selective estrogen receptor modulators. To obtain a greater understanding of how E₂ and selective estrogen receptor modulators differentially regulate genes, it is necessary to investigate their action on a more comprehensive set of native regulatory elements derived from ER target genes. Here we used chromatin immunoprecipitation-cloning and sequencing to isolate 173 regulatory elements associated with ER. Most elements were found in the introns (38%) and regions greater than 10 kb upstream of the transcription initiation site (38%); 24% of the elements were found in the proximal promoter region (<10 kb). Only 11% of the elements contained a classical estrogen response element; 23% of the elements did not have any known response elements, including one derived from the naked cuticle homolog gene, which was associated with the recruitment of p160 coactivators. Transfection studies found that 80% of the 173 elements were regulated by E₂, raloxifene, or tamoxifen with ER or ERβ. Tamoxifen was more effective than raloxifene at activating the elements with ER, whereas raloxifene was superior with ERβ. Our findings demonstrate that E₂, tamoxifen, and raloxifene differentially regulate native ER-regulatory elements isolated by chromatin immunoprecipitation with ER and ERβ.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Coregulators:   SRC-1  |  GRIP1  |  AIB1

Ligands:   17β-Estradiol  |  Raloxifene