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Mol Endocrinol. 2016 Jul;30(7):709-32. doi: 10.1210/me.2015-1311. Epub 2016 May 10.

Changes in Gene Expression and Estrogen Receptor Cistrome in Mouse Liver Upon Acute E2 Treatment.

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Equipe Spatio-Temporal Regulation of Transcription in Eukaryotes (SP@RTE) (G.P., C.L.P., S.A., G.S., R.M.), Unité Mixte de Recherche 6290 Centre National de la Recherche Scientifique (Institut de Genétique et Développement de Rennes), Université de Rennes 1, Campus de Beaulieu, and Equipe Transcription, Environment and Cancer (TREC) (G.F.), Inserm U1085-Institut de Recherche en Santé, Environnement et Travail, Rennes 35042 Cedex, France; and Equipe 9 "Estrogen Receptor: In Vivo Dissection and Modulation" (A.F., R.S., F.L., C.F., J.-F.A.), Inserm Unité 1048 (Institut des Maladies Métaboliques et Cardiovasculaires), Toulouse 31432 Cedex 4, France.


Transcriptional regulation by the estrogen receptor-α (ER) has been investigated mainly in breast cancer cell lines, but estrogens such as 17β-estradiol (E2) exert numerous extrareproductive effects, particularly in the liver, where E2 exhibits both protective metabolic and deleterious thrombotic actions. To analyze the direct and early transcriptional effects of estrogens in the liver, we determined the E2-sensitive transcriptome and ER cistrome in mice after acute administration of E2 or placebo. These analyses revealed the early induction of genes involved in lipid metabolism, which fits with the crucial role of ER in the prevention of liver steatosis. Characterization of the chromatin state of ER binding sites (BSs) in mice expressing or not ER demonstrated that ER is not required per se for the establishment and/or maintenance of chromatin modifications at the majority of its BSs. This is presumably a consequence of a strong overlap between ER and hepatocyte nuclear factor 4α BSs. In contrast, 40% of the BSs of the pioneer factor forkhead box protein a (Foxa2) were dependent upon ER expression, and ER expression also affected the distribution of nucleosomes harboring dimethylated lysine 4 of Histone H3 around Foxa2 BSs. We finally show that, in addition to a network of liver-specific transcription factors including CCAAT/enhancer-binding protein and hepatocyte nuclear factor 4α, ER might be required for proper Foxa2 function in this tissue.

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