Androgen receptor and molecular mechanisms of male-specific gene expression

Androgen's central role in male differentiation, fertility and aggression is evident from human pathologies and animal behaviour studies. Androgens directly regulate gene expression via the androgen receptor (AR), a member of the nuclear receptor superfamily. Nuclear receptors share a modular structure, with specialized domains for DNA binding, ligand binding, and transcriptional activation. Ligand-induced conformational changes in receptor trigger coregulators to modify chromatin structure. This in turn controls access of the transcriptional machinery to targeted genes. Given a common receptor structure and mode of action, AR must rely on several mechanisms for transcriptional specificity. As we have shown for the mouse sex-limited protein gene, these include use of divergent DNA binding sites, cooperativity between sites enhanced by intra- and intermolecular interaction of AR's N- and C-termini, and coactivator interactions. Although individual mechanisms lack sufficient specificity or strength, the summed interplay of response elements and accessory factor binding achieves precise gene activation. In addition to direct gene activation, AR elicits male-specific expression by modulating other hormonal pathways. For example, androgen control of growth hormone secretion induces male-specific genes in the liver. This sex-specific expression is further enforced by a novel class of KRAB zinc finger repressors. Their variation between species evidences diverging mechanisms of sexual differentiation, echoing AR's own recent origin.