# RNA-mediated Chromatin Regulation and Transgenerational Epigenetic Inheritance in C. elegans

> **NIH NIH R35** · RUTGERS, THE STATE UNIV OF N.J. · 2024 · $392,500

## Abstract

Project Summary/Abstract:
Nuclear RNAi is an evolutionarily conserved epigenetic silencing pathway that targets transposons and other
foreign DNA. The defining features of this pathway are small RNA-guided chromatin modifications and
transcriptional repression at a target gene. In C. elegans, nuclear RNAi is essential for genome stability and
promotes germline immortality. Nuclear RNAi can be conveniently triggered by feeding worms with dsRNA,
which leads to heritable silencing at the target gene for multiple generations. These features, together with
powerful genetics and genomic tools and a three-day reproductive cycle, make C. elegans a highly tractable
system to study transgenerational epigenetic inheritance (TEI) in animals. Project 1. Investigating the
biochemistry and cellular function of a novel histone modification H3K23me3. The broad and long-term
objectives of this project are to comprehensively identify and characterize the histone post-translational
modifications and corresponding chromatin enzymes in the context of TEI. In the proposed funding cycle, this
application will investigate the function and enzymology of a novel histone modification H3K23me3, which can
be induced by nuclear RNAi. H3K23me3 is an understudied heterochromatin mark even though it is conserved
from plants to mammals. This application will take combined genetic, genomic, and biochemical approaches to
(1) determine the functional relationship between three key heterochromatin marks: H3K9me3, H3K23me3,
and H3K27me3, (2) understand why the nuclear RNAi pathway is required for C. elegans germline immortality
under heat stress, and (3) identify additional H3K23 histone methyltransferases in C. elegans. The results will
advance the histone code theory and provide mechanistic insight into nuclear RNAi and TEI. Project 2.
Investigating how C. elegans germline distinguishes self and nonself siRNAs. The broad and long-term
objectives of this project are to dissect the diverse functions of small RNAs in C. elegans and understand how
cells distinguish self and foreign genetic material. As a short-term goal, this project will investigate a newly
identified genetic activity termed “siRNA suppression”, which enables C. elegans to distinguish siRNAs that
target self-genes from ones that target nonself DNA such transposons. Both classes of siRNAs play important
but different functions in animal development. This project will identify the protein factors, subcellular location,
and molecular rules of siRNA suppression. As an overall significance, this application will identify new
components in chromatin and small RNA, both of which are fundamental to our understanding of
transgenerational epigenetics and long-term environmental impacts on human health.

## Key facts

- **NIH application ID:** 10764484
- **Project number:** 1R35GM152219-01
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** Guoping Gu
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $392,500
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764484

## Citation

> US National Institutes of Health, RePORTER application 10764484, RNA-mediated Chromatin Regulation and Transgenerational Epigenetic Inheritance in C. elegans (1R35GM152219-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10764484. Licensed CC0.

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