Evolving chromatin functions through metabolic enzymes

University Of California-San Diego, La Jolla CA

Investigators

Abstract

The 23 pairs of chromosomes that carry human genetic information contain both DNA and proteins that package the genome to protect it and regulate its use within cells. This protein-DNA material, known as chromatin, and the complex linear chromosomes, are very different than genetic packaging in simpler organisms like bacteria, which ordinarily carry their genomes on a single, circular molecule. It has become increasingly clear that chromatin-based processes are deeply tied to ancient metabolic activities. Understanding these links, including defining novel, unsuspected functions of metabolic enzymes, holds the promise of revealing critical aspects of the evolution of genomic processes and stability. Major impact of the project comes from the training opportunity provided for the students and fellows performing the research. They will participate in frontline interdisciplinary research to foster both experimental and computational skills. Importantly, the students and fellows will contribute to the lab's work to promote diversity in science through mentoring high school and undergraduate students identified through outreach programs, including students transferring to UCSD from the community college system, a population with a significant component of first-generation and under-represented college students. The participation of these students in a mentored and meaningful research program will contribute to the development of a more highly trained and diverse scientific community for the 21st century. The long-term goal of the proposed research is to define the chromatin-directed functions of metabolic enzymes with previously unsuspected functions in epigenetic transcriptional silencing and DNA damage repair. These studies build upon progress with the model eukaryote, Saccharomyces cerevisiae in which, in proof of principle studies, the investigators discovered previously unsuspected nuclear roles for two enzymes with earlier defined functions in amino acid metabolism. The objectives for the research are to define chromatin-directed functions of a panel of newly identified metabolic enzymes with nuclear roles, using the strategies that the investigators have successfully developed. By probing long known but incompletely understood metabolic enzymes, the progress made in this research will be of fundamental significance defining proteins that have contributed to the molecular and cellular evolution of nuclear processes in the course of genomic evolution. Significantly, study of these enzymes will establish a framework defining the interplay between metabolism and chromatin functions that are critical for gene regulation, response to DNA damage, and maintenance of genome stability. The project employs a combination of classical functional studies, genome-scale analysis and newly developed microfluidics and single-cell imaging technologies that enable visualization of the silencing dynamics in single cells.