Many biological processes, including the regulation of cell growth, differentiation, and development are driven by fixed patterns of gene expression. In order to understand how these normal cellular and organismal processes progress, as well as how they go awry in various disease states, it is paramount to comprehend the basics of how transcription can be regulate in mammalian cells. All cellular genes are regulated within a chromatin context, and it has long been appreciated that chromatin plays a central role in determining the activation state of a gene. Condensed chromatin is known to inhibit both the initiation and elongation of transcription by RNA polymerase. Induction of gene expression therefore often requires remodeling of the chromatin to a more extended configuration, so that it becomes accessible both to specific DNA-binding in the active chromatin state in order to efficiently express a gene. Recently, specific proteins or complexes of proteins have been identified that have the capability to alter chromatin structure. In particular, we and others have shown that the highly conserved HMG-14/-17 family of proteins can both alter higher order chromatin structure and facilitate transcription by RNA polymerase II and III. In the proposed study, we will investigate the molecular mechanism, via chromatin alterations, of transcriptional induction by HMG-14. In particular, we will determine whether the transcriptional activation region of HMG-14 alers histone H1-chromatin interactions and whether the binding of transcriptionally active HMG-14 specifically interacts with DNA-binding transcription factors. These studies should lay the groundwork for understanding a potentially novel mechanism for mediating transcriptional induction by reconfiguring the structure of chromatin at specific genes.
