Figure 2. Genomic occupancy of GR monomers and dimers regulates gene transcription.

(A) Under normal physiological settings, cortisol enables GR to activate transcription through monomeric and dimeric interaction with half-site and palindromic motifs scattered throughout the genome. Neither monomers nor dimers can efficiently access motifs buried in repressive chromatin. Thus, most of their binding sites reside in open chromatin established by lineage determining TFs. Genomic occupancy is tilted toward monomers given that monomeric sites outnumber dimeric by 5:1 in liver. (B) In response to GC drugs, induced gene expression is associated with increased GR occupancy at dimeric sites, whereas down-regulated and unchanged genes correlate with a concomitant loss of GR at monomeric sites. While the genome-wide balance remains tilted toward monomers, gain of occupancy at one set of sites at the expense of another suggests a squelching mechanism for GC-mediated repression of gene expression. Indirect repression can also result from the primary induction by dimeric GR of genes whose products repress transcription. Genomic data do not support a mechanism for direct GC-mediated repression.