# The Molecular and Regulatory Mechanism of m6A mRNA Modification

> **NIH NIH R35** · JACKSON LABORATORY · 2020 · $425,000

## Abstract

PROJECT SUMMARY/ABSTRACT
RNA modifications influence RNA expression and function without changing the underlying nucleotide
sequence. N6-methyladenosine (m6A) is the most abundant mRNA internal modification, existing in thousands
of mRNAs, of which the majority encode for regulatory proteins such as transcription factors. Although
emerging evidence links m6A to stem cell differentiation, neurological disease and cancer, the molecular and
regulatory mechanisms of m6A are poorly understood. To begin to address this significant knowledge gap, I
previously developed the m6A-CLIP method to precisely map m6A modifications in mRNAs genome-wide,
enabling the direct examination of m6A function in a site-specific manner. We discovered that m6A addition is
part of mammalian pre-mRNA synthesis. We also showed that site-specific mutation of m6A sites leads to
increased mRNA half-life in the cytoplasm. Thus, my work in the last five years has established a completely
new role for m6A as an important link between nuclear events that occur on nascent pre-mRNA and
cytoplasmic events that determine mRNA stability. These findings provide the premise for the current proposal
and they uniquely position my interdisciplinary research program to carry out the proposed studies. Here, our
objectives are to identify the molecular mechanisms regulating m6A site-specific deposition and m6A function in
cytoplasmic mRNA stability. We will reach these objectives by biochemical characterization of the m6A protein
complexes. We will also perform genome-wide CRISPR interference screening to systematically identify m6A
regulators. Finally, we will build a data-driven computational model to predict m6A site-specific deposition and
its effects in cytoplasmic mRNA turnover. Thus, successful completion of the proposed work will systematically
reveal the underlying mechanisms of m6A RNA biology by combining cutting edge computational biology,
innovative biochemistry and high-throughput genetics. These findings are expected to have a transformative
impact on the RNA field by stimulating further studies into the role of mRNA modifications in regulating gene
expression. Our long-term goal is to leverage the mechanistic information learned herein to gain deep insights
into the role of m6A in human disease and to design novel mRNA modification-targeted therapeutics that
regulate gene expression without altering the host genomic sequence.

## Key facts

- **NIH application ID:** 9982384
- **Project number:** 5R35GM133711-02
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** Shengdong Ke
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,000
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982384

## Citation

> US National Institutes of Health, RePORTER application 9982384, The Molecular and Regulatory Mechanism of m6A mRNA Modification (5R35GM133711-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9982384. Licensed CC0.

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