Palierne G et al.
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 extra-reproductive 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 following 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 4 α (Hnf4α) BSs. In contrast, 40% of the BSs of the pioneer factor Foxa2 were dependent upon ER expression, and ER expression also affected the distribution of nucleosomes harboring dimethylated H3K4 around Foxa2 BSs. We finally show that, in addition to a network of liver-specific transcription factors including Cebpα/β and Hnf4α, ER might be required for proper Foxa2 function in this tissue.