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Unique ER Cistromes Control Cell Type-Specific Gene Regulation

Division of Molecular and Cellular Oncology (S.A.K., M.L., J.E., M.B.), Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115; Departments of Obstetrics and Gynecology and Biological Chemistry (G.A.M.-C.), David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095; and Cancer Research UK (J.S.C.), Cambridge Research Institute, Robinson Way, Cambridge CB2 0RE, United Kingdom

Address all correspondence and requests for reprints to: Myles Brown, Dana-Farber Cancer Institute, 44 Binney Street, D730, Boston Massachusetts 02115. E-mail: myles_brown{at}dfci.harvard.edu.

Estrogens play an important role in normal physiology and in a variety of pathological states involving diverse tissues including breast and bone. The mechanism by which estrogens exert cell type- and disease-specific effects, however, remains to be explained. We have compared the gene expression profile of the MCF7 breast cancer cell line with that of the osteoblast-like cell line U2OS-ER by expression microarrays. We find that fewer than 10% of the 17β-estradiol (E2)-regulated genes are common to both cell types. We have validated this in primary calvarial osteoblasts. To dissect the mechanism underlying the cell type-specific E2 regulation of gene expression in MCF7 and U2OS-ER cells, we compared the ER binding sites on DNA in the two cell types by performing chromatin immunoprecipitation (ChIP) on genomic tiling arrays (ChIP-on-chip). Consistent with the distinct patterns of E2-regulated gene expression in these two cell lines, we find that the vast majority of ER binding sites are also cell type specific and correlate both in position and number with cell type-specific gene regulation. Interestingly, although the forkhead factor FoxA1 plays a critical role in defining the ER cistrome in MCF7 cells, it is not expressed in U2OS-ER cells, and forkhead motifs are not enriched in the ER cistrome in these cells. Finally, the ER cistromes are correlated with cell type-specific epigenetic histone modifications. These results support a model for the cell type-specific action of E2 being driven primarily through specific ER occupancy of epigenetically marked cis-regulatory regions of target genes.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol

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