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Abstract:
The glucocorticoid (GR) and androgen (AR) receptors execute unique functions in vivo, yet have nearly identical DNA binding specificities. To identifymechanisms that facilitate functional diversification among these transcription factor paralogs, we studied AR and GR in an equivalent cellular context.Analysis of chromatin and sequence features suggest that divergent binding, and corresponding gene regulation, aredriven by different abilities ofAR and GR to interact with relatively inaccessible chromatin. Divergent genomic binding patterns can also be the results ofsubtle differences in DNA binding preferencebetween AR and GR. Furthermore, the sequence composition of large regions (>10 kb) surrounding selectively occupied binding sites differssignificantly,indicating a role for the sequence environment in selectively guiding AR and GR to distinctbinding sites. The comparison of binding sites that are shared between AR and GR shows that the specificity paradox can also be resolved by differences in the events that occur downstream of receptor binding. Specifically, we find that shared binding sites display receptor-specific enhancer activity, cofactor recruitment and changes in histone modifications.Genomic deletion of shared binding sites demonstrates their contributiontodirecting receptor-specific gene regulation. Together, these data suggest that differencesin genomic occupancy as well as divergencein the events that occur downstream of receptor binding directfunctional diversification among transcription factor paralogs.
