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

> **NIH NIH R01** · RUTGERS, THE STATE UNIV OF N.J. · 2020 · $357,243

## Abstract

PROJECT SUMMARY:
Nuclear RNAi is an evolutionarily conserved pathway in which small interfering RNAs (siRNAs) guide
chromatin modifications and transcriptional repression. It protects the host genome by epigenetically silencing
transposons and other “non-self” DNA. Since its discovery, nuclear RNAi has provided a powerful paradigm to
study RNA-mediated chromatin regulation and transgenerational epigenetic inheritance. In C. elegans, nuclear
RNAi and heritable silencing can be conveniently triggered by feeding worms with exogenous dsRNA targeting
a native gene. This approach is complemented by investigating molecular events occurring at the endogenous
targets in the C. elegans genome. Using this uniquely tractable system, our published works done in the past
funding cycle have made the following discoveries, which also raised new questions: (1) The heterochromatin
mark H3K9me3 can be functionally decoupled from transcriptional silencing during the maintenance phase.
What is the H3K9me3-independent transcriptional repression mechanism? (2) The heterochromatin enzyme
SET-32 is required for the establishment phase but dispensable for the maintenance phase of RNAi. How does
SET-32 promote silencing establishment? (3) Endogenous targets are transiently expressed in a subset of
germ cells at the proliferation and early meiotic stage in wild type adult animals. What is the mechanism of the
developmental regulation of the low level transcription, and how does it contribute to the reinforcement of
epigenetic silencing memory? (4) When we de-silence endogenous targets of nuclear RNAi, their transcripts
are enriched in germline nuclei. What is the significance of this nuclear localization in triggering RNAi? In the
proposed new funding cycle, we will take both novel and established genetic, biochemical, cell biology, and
computational approaches to answer these questions by achieving the following aims. (1) Investigate the
transgenerational epigenetic mechanisms of silencing establishment. (2) Characterize a novel histone
modification, H3K23me3, and its role in germline nuclear RNAi. (3) Determine the triggering mechanisms at
the endogenous target of nuclear RNAi. The proposed studies, which explore fundamental yet unmapped
territory of modern biology, will advance our understanding of RNA-chromatin interaction, inheritance of
epigenetic states, and genome surveillance, which are all relevant to human development and disease.

## Key facts

- **NIH application ID:** 9972031
- **Project number:** 2R01GM111752-06A1
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** Guoping Gu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $357,243
- **Award type:** 2
- **Project period:** 2014-08-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972031

## Citation

> US National Institutes of Health, RePORTER application 9972031, RNA-mediated Chromatin Regulation and Epigenetic Inheritance in C. elegans (2R01GM111752-06A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9972031. Licensed CC0.

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