# The role of m6A RNA modification as modulator of dsRNA induced cell-intrinsic innate immune responses in hematopoiesis

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $294,800

## Abstract

Project Summary
N6-methyladenosine (m6A) is the most abundant RNA modification and plays key roles in RNA metabolism. m6A
writers and readers are highly expressed in hematopoietic stem and progenitor cells and dysregulated in
myelodysplasia and leukemia.
We show that loss of Mettl3 in hematopoietic stem and progenitor cells (HSPCs) resulted in upregulation of an
anti-viral innate immune response signature as well as marked proliferation and differentiation defects. In
particular, we are the first to report that loss of m6A RNA modification resulted in aberrant dsRNA formation,
leading to activation of the MDA5-RIG-I, PKR-eIF2A, and OAS-RNAse L pathways. By differential
immunoprecipitation of dsRNAs from Mettl3 KO versus WT cells, we identified a specific subset of long, normally
highly m6A modified transcripts with low folding energies, signifying propensity to form extensive RNA secondary
structures. Disruption of innate immune signaling via deletion of Mavs or knockdown of Rnasel in part rescued
colony formation in vitro and engraftment in competitive transplantation assays in vivo. These data suggest that
one of the roles of m6A RNA modifications is to maintain single-strandedness of endogenous RNAs whereby
they mark RNAs as “self” and distinguish them from exogenous pathogen-derived dsRNAs.
In this SHINE II application we propose to dissect the role of m6A RNA modification in HSPCs specifically as it
pertains to its role as suppressor of aberrant innate immune signaling. We will determine the mechanism by
which METTL3-mediated m6A RNA modification prevents abnormal dsRNA formation and consequent induction
of interferon signaling, we will dissect how m6A loss results in a deleterious immune response that disrupts
HSPC function, and we will assess the universality this phenomenon across hematopoietic lineages.

## Key facts

- **NIH application ID:** 10152825
- **Project number:** 1R01DK124788-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Stephanie Halene
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $294,800
- **Award type:** 1
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152825

## Citation

> US National Institutes of Health, RePORTER application 10152825, The role of m6A RNA modification as modulator of dsRNA induced cell-intrinsic innate immune responses in hematopoiesis (1R01DK124788-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10152825. Licensed CC0.

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