Genome-wide analysis of Estrogen Receptor-mediated response to acute Estradiol treatment in liver (ChIP-seq). Mus musculus

Estrogen-based treatments have numerous extra-reproductive effects. On the one hand, they have protective metabolic actions against abdominal fat accumulation, type 2 diabetes, liver steatosis,… But, on the other hand, the oral route of administration, presumably due to a hepatic impact on liver-derived coagulation factors, appears to increase risks of venous thrombosis and pulmonary embolism. The characterization of liver genes expression regulations by these hormones thereby appears of utmost interest, but the estrogen-sensitive transcriptome of liver and ER cistrome was so far explored under chronic hormonal treatment. To explore the early steps of these mechanisms, we determined here the short-term changes in liver transcriptional responses to acute E2 administration, and aimed to characterize the mechanisms allowing these programs to be engaged. Collectively, through the comparison of mice expressing or not ER, our data demonstrate that acute administration of E2 provokes genes expression variations which fit with a crucial role of ER in the prevention of liver steatosis in mice fed with a high fat diet by E2. They also evidenced higher proportion of ER binding sites (BSs) located at the direct vicinity (distance <3kb) of regulated genes than what is determined in human cancer cell models. Besides this specific aspect of ER cistrome in vivo, we unexpectedly found that 40 % of the BSs of the pioneer factor Foxa2 were dependent upon the expression of ER that indirectly influences the distribution of the nucleosomes harbouring a dimethylated H3K4 around these Foxa2 sites. Overall design: Whole-genome analysis of estrogen receptor (ER) and FOXA2 binding events associated with the cartography of two histone marks (H3K4me2 and H3K27ac) in livers from wild-type or ERKO mice.