Molecular Regulation of Epigenetic Inheritance

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In eukaryotes, DNA and histone proteins are packed into a complex structure called chromatin. Chemical modifications of histones play a crucial role in the regulation of chromatin structure and gene expression. These modifications can serve as "epigenetic marks," which are faithfully transmitted through many generations, but the mechanism of inheritance remains poorly understood. The goal of this project is to understand the fundamental principles underlying the inheritance of epigenetic marks. Defects in the regulation of epigenetic marks often result in genomic instability and developmental disorders. Therefore, the study has important implications for several fields, such as agriculture, ecology and medicine. This project will train post-doctoral researchers, graduate students, and undergraduates in genetics and biochemistry. The PI will recruit underrepresented minority and women students to participate in the 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.In the fission yeast, Schizosaccharomyces pombe, histone H3 lysine 9 (H3K9) methylation is enriched in heterochromatin and is stably inherited from generation to generation. The RNA interference machinery (RNAi) also plays a pivotal role in heterochromatin assembly since small interfering RNAs (siRNAs) promote H3K9 methylation. Central to this process is the RITS (RNA-induced transcriptional silencing) complex, which associates with heterochromatin to mediate siRNA generation and heterochromatin silencing. However, how the RITS complex promotes heterochromatin formation behind the replication fork remains unknown. Following up a novel finding that the Dpb4 subunit of DNA polymerase epsilon interacts with Daf2 to promote heterochromatin silencing, the project will (1) determine how Daf2 interacts with heterochromatin transcripts to mediate heterochromatin silencing, (2) determine functional and physical relationship between Dpb4 and Daf2, and (3) determine the role of Daf2 in the recruitment of the RITS complex during DNA replication of peri-centromeric sequences. This study will provide insights into how the RITS complex is recruited on chromatin during DNA replication, which is important for understanding the mechanisms behind epigenetic inheritance of heterochromatin.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.