CAREER: Uncovering small RNA and chromatin modifying pathway interactions that regulate transcriptome homeostasis

Proper coordination of gene regulation is essential to the viability of all organisms. RNA interference (RNAi) and chromatin modifying pathways are dynamic networks critical to regulating the genome and executing cellular programs in all metazoans, including humans. While we understand much about the basic molecular mechanisms of RNAi and chromatin modifying pathways, we know very little about how these interdependent pathways are controlled or interact temporally or spatially.

This project’s overarching goal is to uncover mechanistic details of how the overlapping networks of RNAi and chromatin modifying pathways maintain appropriate gene regulation during stress. Successful completion of the proposed work will advance our understanding of principles of gene regulation and provide key insights into how perturbations to these networks during stress trigger the onset of diseases, such as cancer and infertility.

This project will engage undergraduate and graduate researchers by providing paid early career research opportunities, interdisciplinary training, and establishing a regional scientific seminar series and conference that will provide networking and presentation opportunities for trainees while also exposing them to research outside of their institution.

It is evident RNAi and chromatin modifying pathways collaborate. Prior work has identified chromatin modifying factors required for deposition of repressive chromatin marks at RNAi-targeted loci across eukaryotes. However, our understanding of the intricate mechanisms governing complex interactions between these two essential gene regulatory pathways remains rudimentary.

Using the C. elegans germline as a model system and interdisciplinary approaches (genetics, physiological assays, multi-‘omics approaches, and bioinformatics), we will test the hypothesis that feedback motifs between RNAi and chromatin modifying pathways ensure balance between the pathways to maintain appropriate regulation of a distinct set of genes and protect germ cell identity during heat stress. This project will advance our understanding of (1) the epigenetic and transcriptional landscape of C. elegans germ cells during normal conditions; (2) how RNAi and chromatin modifying pathways collaborate to maintain this landscape during environmental stress; (3) how genetic and environmental perturbations affect gene regulatory pathways; and (4) the molecular mechanisms that maintain balance between these pathways to ensure homeostatic gene regulation.

Moreover, the development of a tool to computationally identify putative feedback motifs using multi-‘omics datasets in any species for any pathway will systematically improve our ability to identify and examine higher-order regulatory motifs that maintain transcriptome homeostasis.

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.