Chromatin accessibility pre-determines de novo steroid receptor binding

Development, differentiation, and response to environmental stimuli are characterized by sequential changes in cellular state initiated by the de novo binding of induced or temporally regulated transcriptional factors to their cognate genomic sites. The mechanism whereby a given regulatory factor selects a limited number of in vivo targets from myriads of potential genomic binding sites is undetermined. Here we show that up to 95% of induced de novo genomic binding by the glucocorticoid receptor4, a paradigmatic ligand-activated transcription factor, is targeted to pre-existing foci of accessible chromatin. Factor binding invariably potentiates chromatin accessibility. Cell-selective de novo genomic occupancy patterns appear to be comprehensively pre-determined by cell-specific differences in baseline chromatin accessibility patterns, with secondary contributions from local sequence features. The results define a novel framework for understanding regulatory factor-genome interactions, and provide a molecular basis for the tissue-selectivity of steroid pharmaceuticals and other agents that intersect the living genome.