# Transgenerational gene silencing

> **NIH NIH R01** · UNIV OF MARYLAND, COLLEGE PARK · 2024 · $322,799

## Abstract

Abstract
Changes that can persist for many generations without altering DNA sequence have been reported in many
organisms. The existence of such heritable epigenetic changes has also been claimed in humans in response
to some stressful experiences such as starvation and psychological trauma. However, there is poor
understanding of the mechanistic basis for the persistence of epigenetic changes across generations in any
organism. Although molecules mediating such changes have been identified in multiple systems (e.g., DNA
methylation, chromatin modifications, small RNAs, etc.), the mere presence of these molecules and chemical
modifications do not predict the persistence of any newly introduced epigenetic change. Recent conceptual
advances that provide a system-level understanding of heredity suggest that changes in regulatory architectures
drive and maintain heritable epigenetic changes. Therefore, focusing on the regulatory architectures can reveal
the important interactions required for explaining any change that can last for multiple generations regardless of
the particular molecules that mediate these interactions. In the nematode C. elegans, multiple phenomena have
been reported whereby RNA-mediated regulation is used to sustain the silencing of gene expression for
hundreds of generations. These phenomena thus provide opportunities for analyzing heritable epigenetic
changes at single-gene resolution to gain insights. In addition to the expected broad applicability of insights into
regulatory architectures, even some of the specific molecules used to regulate heritable epigenetic changes in
C. elegans such as piRNAs, phase-separated RNA granules, the double-stranded RNA importer SID-1, and
small RNA-bound Argonaute proteins are conserved in many organisms, including humans. Our preliminary
results have revealed insights into a regulatory architecture that promotes stable RNA silencing of a model
transgene encoding a fluorescent protein and endogenous genes that are similarly susceptible to heritable
epigenetic changes in gene expression. The aims of this proposal are: (1) to analyze model genes to discover
the regulatory sequences and perturbations that promote transgenerational gene silencing; and (2) to analyze
regulation of endogenous genes to elucidate the regulatory architectures that have evolved to control heritable
epigenetic changes in gene expression within the germline. Completion of these goals will provide both a general
view of heritable epigenetic changes at any gene and reveal the regulatory architecture of evolved mechanisms.
These results will provide a better understanding of hereditary diseases, particularly diseases that could have
an epigenetic origin in earlier generations.

## Key facts

- **NIH application ID:** 10866587
- **Project number:** 5R01GM124356-07
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** Antony Merlin Jose
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $322,799
- **Award type:** 5
- **Project period:** 2018-07-16 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866587

## Citation

> US National Institutes of Health, RePORTER application 10866587, Transgenerational gene silencing (5R01GM124356-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10866587. Licensed CC0.

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