Molecular Regulation of Epigenetic Inheritance

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Intellectual Merit: In eukaryotes, DNA is packaged together with histone proteins into a highly complex structure called chromatin. Chemical modifications to DNA and histones play a key role in the control of chromatin structure and gene expression. These modifications, known as "epigenetic marks", can be faithfully inherited through many generations. During DNA replication, chromatin is disassembled ahead of the replication fork and then reassembled into its original epigenetic state behind the fork. Key questions on how epigenetic marks, particularly histone modifications, are inherited onto newly replicated chromatin, remain poorly understood. The goal of this project is to understand the fundamental principles underlying the inheritance of epigenetic marks. Fission yeast (Schizosaccharomyces pombe) will be used to address this important gap in knowledge. Fission yeast is a simple, genetically tractable model organism that contains many of the epigenetic components present in higher eukaryotes, and has thus recently emerged as a premier model for epigenetic study. In fission yeast, the methylation of histone H3 at lysine 9 (H3K9) is enriched in heterochromatin, the highly condensed and transcriptionally silent part of chromatin. This conserved epigenetic hallmark of heterochromatin is stably inherited from generation to generation, and provides a valuable framework for understanding the mechanisms behind epigenetic inheritance in eukaryotes. In this project, a combination of approaches, including genetics, biochemistry, and cytology, will be used to determine the role of proteins involved in DNA replication in the inheritance of H3K9 methylation. These findings will identify a key mechanistic link between DNA replication and the inheritance of H3K9 methylation, and provide important insights into how these two processes are coupled. This research will contribute to the understanding of the molecular mechanisms governing the inheritance of epigenetic information.Broader Impacts: The epigenetic mechanisms found in S. pombe will likely apply to multicellular eukaryotes. Defects in the regulation of epigenetic marks often result in genomic instability and developmental disorders in both plants and animals. This study thus has important implications for agriculture, ecology and economy. This project will train post-doc researchers, graduate students, and undergraduates in cell biology, genetics, and biochemistry. The PI will continue to recruit underrepresented minority and women students to participate in research. This project will also serve as a teaching resource for courses that the PI teaches at New York University and for an outreach program aimed at encouraging K-12 students to consider careers in science.