# Transgenerational gene silencing by extracellular RNA

> **NIH NIH R01** · UNIV OF MARYLAND, COLLEGE PARK · 2020 · $314,058

## Abstract

Project Summary
Recent epidemiological studies suggest that human health can be influenced by ancestral experience.
Ancestral diet and stress have been identified as possible modifiers of health in descendants. However, the
mechanisms by which the ancestral experience is transmitted to descendants as gene regulatory information
to cause effects is not understood. While RNA and epigenetic modifications have been proposed to correlate
with ancestral experience, the complexity of mammalian biology has presented a challenge to establish causal
mechanisms. In particular, the molecular agent(s) that transmit the information from one generation to the next
and the machinery that promotes changes in gene expression that can be stable for many generations are not
well understood. Identifying such markers of ancestral influence can enable the early diagnosis of susceptibility
to diseases such as obesity and diabetes. We recently found that RNAs exported from neurons in response to
double-stranded RNA (dsRNA) expression can enter germ cells in the nematode C. elegans and silence
matching genes in descendants. Intriguingly, the persistence of this silencing depends on as yet unknown
features of the gene. Because extracellular RNAs are also found in human circulation, they are candidates for
similar transport to the next generation and for triggering subsequent transgenerational effects. In support of
this idea, three key aspects appear to be conserved in mammals including humans: use of a dsRNA-selective
importer for uptake of extracellular dsRNA, use of Argonaute proteins for gene silencing, and use of histone
modifications for stable propagation of the regulatory state of a gene. The goal of this proposal is to understand
mechanisms that regulate the ability of extracellular RNA in ancestors to affect genes of matching sequence in
descendants. We will determine the features of extracellular RNA that enable it to trigger transgenerational
gene silencing using cell biological and genetic approaches. We will determine the factors that make a gene
susceptible to transgenerational changes in gene regulation using forward genetic, genome editing, and
epigenome editing approaches. Finally, we will identify and validate loci in the C. elegans genome that are
susceptible to ancestral influences using insights that we have gained from the silencing of a model gene by
dsRNA exported from ancestral neurons. These studies will provide a clear picture of mechanisms that can
promote or inhibit gene regulation by inherited RNAs in an animal, which are likely to be extendable to other
animals including mammals.

## Key facts

- **NIH application ID:** 9894814
- **Project number:** 5R01GM124356-03
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** Antony Merlin Jose
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $314,058
- **Award type:** 5
- **Project period:** 2018-07-16 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894814

## Citation

> US National Institutes of Health, RePORTER application 9894814, Transgenerational gene silencing by extracellular RNA (5R01GM124356-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9894814. Licensed CC0.

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