Regulation of oestrogen receptor gene expression: new insights and novel mechanisms

17Beta-oestradiol is a pleiotropic hormone with organisational, activational and protective actions in both male and female mammals. It is responsible for numerous aspects of brain development, including sexual differentiation of the brain. The organisational effects of early oestrogen exposure are essential for long-lasting cognitive and behavioural functions. Oestradiol mediates its effects through several intracellular or membrane-associated receptor proteins. In the rodent cerebral cortex, oestrogen receptor (ER) expression, as demonstrated by hormone binding studies, is high early in postnatal life and declines precipitously as the animal approaches puberty. This decline is caused by a decreased expression of ERalpha mRNA. An understanding of the mechanisms involved in the regulation of ERalpha gene expression is critical for understanding the developmental as well as postpubertal expression of the ER. Despite recent data indicating the current hormone replacement therapies can be detrimental in older women, numerous animal studies have shown that the endogenous oestrogen, 17beta-oestradiol, is neuroprotective. Specifically, low levels of oestradiol protect the cortex from cell death caused by middle cerebral artery occlusion (MCAO). The attenuation of cell death by oestradiol in this model is mediated through an ERalpha-dependent mechanism. To this end, ERalpha expression is rapidly increased after MCAO, suggesting a return to the developmental programme of gene expression within neurones. One mechanism of suppressing gene expression is by the epigenetic modification of the promoter regions, which results in gene silencing. Of the epigenetic modifications utilised by cells, DNA methylation has been intensively studied as a mechanism by which genes are both permanently and reversibly silenced. Little is known about the mechanisms of ER gene regulation in the brain; however, in breast cancer cells, both ERalpha and ERbeta are down-regulated by promoter methylation, and subsequent binding of the methyl-CpG-binding protein, MeCP2. Data from our laboratory demonstrate that the promoters of the ERalpha gene are also methylated during development and after neuronal injury, suggesting a role of DNA methylation in regulating ER expression in the brain.