Gordon Francesca K, Vallaster Caroline S, Westerling Thomas, Iyer Lakshmanan K, Brown Myles, Schnitzler Gavin R
Molecular Cardiology Research Institute (F.K.G., C.S.V., L.I.K., G.R.S.), Tufts Medical Center, Boston, Massachusetts 02111; and Medical Oncology Department (M.W. M.B.), Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Mol Endocrinol. 2014 Aug;28(8):1337-51. doi: 10.1210/me.2013-1395. Epub 2014 Jul 3.
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 α (ERα) transcription factor. Here, through next-generation sequencing approaches, we show that almost all of the genes regulated by 17β-estradiol (E2) differ between mouse aorta and mouse liver, ex vivo, and that this difference is associated with a distinct genomewide distribution of ERα on chromatin. Bioinformatic analysis of E2-regulated promoters and ERα binding site sequences identify several transcription factors that may determine the tissue specificity of ERα binding and E2-regulated genes, including the enrichment of NF-κB, AML1, and AP1 sites in the promoters of E2 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.
雌激素对绝经前女性以及接受激素替代疗法的60岁以下女性具有血管保护作用。然而，雌激素也会增加乳腺癌、子宫癌以及与肝脏中凝血因子上调相关的静脉血栓形成的风险。在小鼠模型中，雌激素的血管保护作用是由雌激素受体α（ERα）转录因子介导的。在此，通过下一代测序方法，我们发现，在体外，小鼠主动脉和小鼠肝脏中几乎所有受17β-雌二醇（E2）调控的基因都存在差异，并且这种差异与ERα在染色质上独特的全基因组分布有关。对E2调控的启动子和ERα结合位点序列进行生物信息学分析，确定了几种可能决定ERα结合和E2调控基因组织特异性的转录因子，包括主动脉而非肝脏中E2下调的炎症基因启动子中NF-κB、AML1和AP1位点的富集。这些因子可能具有的血管特异性功能提示了在不引起其他组织负面效应的情况下，促进雌激素在血管系统中发挥保护作用的方法。
