Schematic representation of the genomic effect of estradiol. Nuclear translocation of ligand-bound receptor. (A) Activation of targeted genes in osteoblasts necessitates recruitment of two chromatin remodeling complexes known as SWI/SNF-A (switching defective/sucrose nonfermenting), as well as coactivators of the p160 family including SRC-1, SRC-2, and SRC-3 (steroid receptor coactivators 1, 2, and 3). All of the SRCs possess three nuclear receptor (NR) boxes located in the receptor interacting domain, which enables direct interaction with ERα; and two activation domains, AD1 and AD2, which serve as binding sites for p300/CBP (cointegrator-associated protein), and CARM1 (coactivator-associated arginine methyltransferase 1). The importance of these coregulators, especially p300/CBP, relates to the latter’s interaction with the AF-2 domain of the ERs, which prompts recruitment of histone acetylases to the receptor. Together with the SRC complexes, the epigenetic enzyme disrupts DNA stability, thus allowing transcription of the target genes. (B) Repression of transcription occurs in a manner opposite to that of activation. Upon SERM binding, the receptor undergoes conformational changes that enhance interactions with corepressors. Three of the most well-known repressors of ERα-mediated transcriptional activity are NCoR (nuclear corepressor), silencing mediator of retinoid and thyroid receptor (SMRT), and repressor of ERα activity (REA). This transcriptional comodulatory apparatus results in inhibition of transcription.
