23rd Annual Genetics Day
University of Rochester Medical Center
Friday, May 6, 2011
9th Annual Fred Sherman Lecture, Dr.
Keith R. Yamamoto
"Transcriptional Regulation by Steroids:
Signal Integration and Gene Networks"
Abstract: What mechanisms govern transcriptional regulation in metazoans, where a single regulatory factor can control distinct gene networks in different tissues, in different developmental phases, in different physiological or pathological settings? The remarkable cell- and gene-specificity of transcriptional regulation by steroid hormone receptors such as the glucocorticoid receptor (GR) reflect their capacity to integrate the effects of multiple signals, including hormones, high-affinity DNA binding sequences, cellular cofactors and covalent modifications. Allosteric transitions-- conformational changes transduced through receptors from “signal reception surfaces” to “signal effector surfaces”— appear to impart regulatory specificity. Thus, small chemical variations in hormonal ligands can specify the selectivity of GR:GRE occupancy, or modulate the regulatory activity of a GR:GRE complex. Similarly, 15 bp GR binding sequences (GBSs) differing by as little as a single base pair differentially affect GR conformation and regulatory activity. Using structural, molecular, bioinformatic and genetic analyses, we have identified GBS-specific conformational shifts in GR that are likely responsible in part for differences in the composition and function of regulatory complexes whose assembly is nucleated upon the GR:GRE interaction. DNA-driven protein allostery is a one mechanism by which transcriptional regulatory factors tailor their activities at specific target genes, thus producing distinct networks of regulated genes.