CAREER: HP1 protein functions in gene regulation and chromatin structure

University Of Alabama At Birmingham, Birmingham AL

Investigators

Abstract

The goal of this project is to understand the molecular mechanisms that determine if the genetic information contained within DNA is accessible to the cellular machinery. DNA in a cell's nucleus is packaged into a complex structure called chromatin, which contains a variety of proteins. These chromatin proteins determine if the information stored in a particular portion of the DNA is accessible (genes are "turned on") or inaccessible (genes are "turned off") as part of a process called gene regulation. The members of the Heterochromatin Protein 1 (HP1) protein family function in chromatin structure in organisms as diverse as yeast and humans. Specifically, this project will examine the role of HP1 proteins in gene regulation and the molecular mechanisms mediating this role. It is essential for an organism's survival and health to "turn on" the correct genes at the correct time and place. The results from this study will improve scientific understanding of why this process sometimes goes wrong and how it might be corrected. In addition to furthering knowledge about chromatin, this study will serve to train minority students in chromatin biology through a summer internship program and support the development of a classroom undergraduate research experience (CURE) specifically targeted to minorities and non-traditional students transferring from community colleges to four-year institutions. This project will use transcriptome analysis of Drosophila lines lacking HP1 proteins and chromatin state information from chromatin immunoprecipitation (ChIP) experiments to evaluate the impact of HP1 proteins on gene expression. This analysis will reveal the contexts in which HP1 proteins function as transcriptional activators or repressors, and how cooperative effects differ from individual effect. Analysis of the impact of HP1 recruitment on nucleosome positioning, chromatin composition, and RNA polymerase dynamics will determine how HP1 proteins impact gene regulation. These experiments will identify the molecular mechanism(s) mediating the effects of HP1 proteins on gene expression. Finally, biochemical analysis of the transcription-start-site-(TSS)-associated HP1 complexes will determine why single HP1 complexes are formed at some TSSs, while others recruit multi-HP1 complexes. The findings will provide the foundation for understanding how this important class of proteins is recruited to their target sites and carries out diverse functions in chromatin structure and gene regulation. By utilizing a multi-faceted approach, this study will link the well-established role of HP1 proteins in heterochromatin formation with their role in gene regulation. This project is co-funded by the Genetic Mechanisms Program in the Division of Molecular and Cellular Biosciences in the Biological Sciences Directorate and by the NSF EPSCoR Program.