Dynamic regulation of estrogen receptor-alpha gene expression in the brain: a role for promoter methylation?

Estrogen has long been known to play an important role in coordinating the neuroendocrine events that control sexual development, sexual behavior and reproduction. Estrogen actions in other, non-reproductive areas of the brain have also been described. It is now known that estrogen can also influence learning, memory, and emotion and has neurotrophic and neuroprotective properties. The actions of estrogen are largely mediated through at least two intracellular estrogen receptors. Both estrogen receptor-alpha and estrogen receptor-beta are expressed in a wide variety of brain regions. Estrogen receptor-alpha (ERalpha), however, undergoes developmental and brain region-specific changes in expression. The precise molecular mechanisms that regulate its expression at the level of gene transcription are not well understood. Adding to the complexity of its regulation, the estrogen receptor gene contains multiple promoters that drive its expression. In the cortex in particular, the ERalpha mRNA expression is dynamically regulated during postnatal development and again following neuronal injury. Epigenetic modification of chromatin is increasingly being understood as a mechanism of neuronal gene regulation. This review examines the potential regulation of the ERalpha gene by such epigenetic mechanisms.