# Investigation of RNA interference and related gene regulatory mechanisms

> **NIH NIH R35** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $115,156

## Abstract

PROJECT SUMMARY
Over evolutionary time, species access innovations that evolve in parallel lineages. The mitochondrion and
chloroplast genome-transfers provide stunning examples. The experimental transfer of DNA has begun to
provide a glimpse at—and a handle to explore—this fundamental process. C. elegans, whose rapid life cycle
calls upon the germline to function every few days, is an ideal animal in which to investigate transgenerational
systems that regulate information. This project will explore the following questions: 1) How do cells distinguish
‘licensed’ from potentially dangerous ‘unlicensed’ information? 2) How do Argonautes and chromatin regulators
coordinate to propagate gene-expression states? 3) How do distinct Argonaute systems integrate to achieve
surveillance and how is transcriptome surveillance organized spatially? A remarkable feature of RNA surveillance
in the worm germline is that both silenced and expressed states are communicated to offspring via small RNAs.
These small-RNA signals comprise approximately one million different guide-RNA species that engage a dozen
different germline Argonautes. Initiators of silencing—e.g., dsRNA, piRNAs, and recently intronless mRNAs—
have been relatively easy to identify. Yet, insights into mechanisms that ensure pathway specificity have been
elusive. Moreover, the coordination between small RNA pathways and heterochromatin remains murky.
Preliminary studies suggest that peri-nuclear nuage domains marked by RNA-binding proteins differentiate from
each other to direct distinct RNA-silencing tasks, and nuage domains appear to communicate or associate with
the small-RNA source loci in the nucleus. This compartmentalization could dramatically simplify the math for
whole transcriptome silencing. Instead of millions of guide complexes in each nuage domain, only about 20,000
distinct guide-RNA species would be needed to silence adjacent heterochromatin. Understanding the cascading
effects that shift the balance of RNA binding and surveillance in nuage and heterochromatin could shed light on
related perturbations that cause a myriad of human disorders.

## Key facts

- **NIH application ID:** 10842794
- **Project number:** 1R35GM153442-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** CRAIG C MELLO
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $115,156
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842794

## Citation

> US National Institutes of Health, RePORTER application 10842794, Investigation of RNA interference and related gene regulatory mechanisms (1R35GM153442-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10842794. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*