Research Resource: Aorta- and Liver-Specific ERα-Binding Patterns and Gene Regulation by Estrogen

Estrogen has vascular protective effects in premenopausal women and in women younger than 60 years who are receiving hormone replacement therapy. However, estrogen also increases the risks of breast and uterine cancers and of venous thromboses linked to up-regulation of coagulation factors in the liver. In mouse models, the vasculoprotective effects of estrogen are mediated by the estrogen receptor alpha (ER alpha) transcription factor. Here, through next-generation sequencing approaches, we show that almost all of the genes regulated by 17 beta-estradiol (E-2) differ between mouse aorta and mouse liver, ex vivo, and that this difference is associated with a distinct genome-wide distribution of ER alpha on chromatin. Bioinformatic analysis of E-2-regulated promoters and ER alpha binding site sequences identify several transcription factors that may determine the tissue specificity of ER alpha binding and E-2-regulated genes, including the enrichment of NF-kappa B, AML1, and AP1 sites in the promoters of E-2 down-regulated inflammatory genes in aorta but not liver. The possible vascular-specific functions of these factors suggest ways in which the protective effects of estrogen could be promoted in the vasculature without incurring negative effects in other tissues.