We have elaborated a model of gene regulation (hit-and-run) based on the surprising finding that receptors and several of their coregulators exchange rapidly with regulatory elements in living cells. These proposals have led to a major paradigm shift in the field. The model has been extended to describe interactions of the androgen receptor with chromatin templates in vivo and in vitro, confirming that the general concept is broadly valid across the nuclear receptor superfamily. We compared the in vivo ligand effects with the ability of AR to carry out chromatin remodeling at the MMTV promoter in vitro. Agonist liganded receptor supported SWI/SNF dependent, ATP dependent, displacement of the receptor from a reconstituted nucleosome template during the chromatin remodeling reaction. These findings indicate that mobility of the receptor on and off the chromatin template is directly coupled to chromatin remodeling, and links this mechanism to receptor movement in the nucleus. An outcome predicted by the hit-and-run hypothesis is the potential modification of receptor activity during the process of hormone induction. We discovered (Qiu et al, Molecular Cell 2006) that HDAC1 is a coactivator for GR action, that the enzyme is acetylated after association with the glucocorticoid receptor, and that the deacetylase activity of the enzyme is strongly inhibited by the acetylation event. We also found that the acetylated form of the enzyme is associated with repressed chromatin while HDAC1 found in active chromatin fragments manifests low acetylation levels, and concluded that active acetylation of HDAC1 is a key event in the regulation of gene activity by nuclear receptors. This work presents a another major paradigm change in the field of gene regulation. HDACs are currently viewed primarily as corepressors, serving in many complexes that are associated with silenced genes. Our work demonstrates that HDAC1 is a coactivator for GR mediated regulation, and introduces the novel concept of modification of HDAC activity by acetylation. This modification occurs progressively during hormone induction, and provides a new mechanistic basis for the phenomenon of promoter cycling, recently described for several nuclear receptors. HDACs are frequent members of complexes that are perturbed in cancer cells. Thus, this new concept will have important ramifications not only for mechanisms of gene regulation, but also in the broader field of cancer biology, and has attracted wide attention in the community.
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