479590 Investigation of the HP1-SUV39H1 Interaction in S. Cerevisiae

Monday, November 14, 2016
Grand Ballroom B (Hilton San Francisco Union Square)
Elaine Indermaur and Albert Keung, Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC

The eukaryotic genome exists as chromatin, a complex structure of DNA wrapped around octamers of histone proteins called nucleosomes. Biochemical modifications to N-terminal histone tails, including methylation and acetylation, help control eukaryotic gene expression, thereby regulating a variety of cellular processes. One important modification, methylation of histone H3 lysine 9 (H3K9), contributes to the generation of silent heterochromatin and has recently been implicated in the silencing of tumor suppressor genes and cancer. In humans, SUV39H1 is an H3K9 methyltransferase, and the protein HP1 interacts with SUV39H1 to help establish large, stable domains of methylated H3K9. The drug chaetocin is thought to inhibit the methyltransferase activity of SUV39H1and could be a potential anti-cancer drug. A better understanding of the molecular interactions between HP1, SUV39H1, and chaetocin is necessary to both illuminate chromatin-based transcriptional regulation and stimulate the downstream development of anti-cancer drugs that target cancer-causing chromatin modifications. Additionally, a better understanding of chromatin-based transcriptional control could result in novel gene regulation techniques for cellular engineering. Previous studies in natural cellular systems as well as in vitro approaches provide a wealth of knowledge about this heterochromatin system but cannot avoid either pleiotropic effects within cells or non-physiological conditions in vitro. Therefore, we have developed a synthetic two-hybrid system in Saccharomyces cerevisiae, a eukaryotic species that naturally lacks H3K9 methylation and its associated heterochromatin system. Our system has verified the direct interaction between specific domains of HP1 and SUV39H1 in living cells. Interestingly, we found that chaetocin, originally thought to inhibit the H3K9 methyltransferase activity of human SUV39H1, actually inhibits the interaction between SUV39H1 and HP1 and may therefore function through this mechanism to ablate heterochromatin formation. Our work has provided insights into the molecular interactions of an important heterochromatin system and provided new insights into a class of potential anti-cancer compound. Furthermore, the approach we have developed could be harnessed as a unique gene regulatory system for cellular engineering and biotechnology applications in yeast.

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