Laboratory of Molecular Carcinogenesis; NIEHS
Steroid hormone dependent systems have proved particularly valuable as tools to explore the mechanistic frameworks that cells use to control gene expression. The precise folding of DNA into chromatin provides multicellular organisms with sophisticated mechanisms of gene regulation. In addition, the presence of post replicative and posttranslational "marks" or "tags" on DNA and histones further expands and refines the mechanism available to the cell. This results in an amplification of the inherent genetic information contained in the four nucleotides that comprise DNA. Consequently, mechanisms to "extract" and use this information are critical to understanding normal growth and development as well as disease.
We have exploited the Mouse Mammary Tumour Virus (MMTV) regulatory sequences as a model for understanding the role of chromatin and epigenetics in gene regulation. We have shown that chromatin remodelling proteins are required for efficient gene transcription in living cells. The chromatin architecture serves to restrict the binding of ubiquitous general transcription factors to maintain the basal state. Previous studies have identified the BRG1 chromatin-remodelling complex as the specific and critical molecular machine required to disrupt promoter structure in response to glucocorticoids. However, the ability of chromatin remodelling proteins to disrupt the promoter architecture is itself regulated by epigenetic modification of the core histones at the promoter. In recent studies, we have ascribed specific functions for subunits of the remodelling complex as well as novel intramolecular functions to the BRG1 ATPse component. In combination with studies describing effects of specific histone modifications, we begin to develop a picture of epigenetic and chromatin contributions to the hormonal regulation of gene transcription.