# Dysregulated Adenosine Methylation of mRNA as a Novel Mechanism of Heart Failure

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $423,750

## Abstract

TITLE: Dysregulated Adenosine Methylation of mRNA as a Novel Mechanism of Heart Failure
PROJECT SUMMARY:
One of most exciting advancements in the RNA field is the recent discovery that post-transcriptional
modifications of mRNAs (epitranscriptome) are vital to several cellular processes including mRNA stability,
nuclear export, cellular compartmentalization, splicing, translation and their degradation. However, function of
the epitranscriptome remains unexplored in mature post-mitotic tissues such as the mammalian heart
especially under the pathophysiological remodeling. Discrepancies in expression levels of mRNAs and proteins
in the hearts of heart failure patients implicate a major role for the cardiac epitranscriptome in protein expression.
Therefore, addressing this lack of mechanistic insight and understanding the pathomechanisms of yet unexplored
epitranscriptomic regulations underlying cardiac remodeling are of major clinical interest. In a first-of-its kind
approach, we studied the cardiac epitranscriptome and focused our investigation on N6-methyladenosine
(m6A), the most prevalent and functionally relevant chemical modification in mRNA. We discovered that m6A-
containing mRNA is significantly increased during ischemic cardiac remodeling, associated with the loss of an
m6A demethylase, fat and obesity-associated protein (FTO). We discovered FTO as a critical regulator of m6A
methylation in the heart during cardiac remodeling. Post-ischemic loss of FTO is associated with a cascade of
biological alterations including increase in m6A methylation, altered mRNA, miRNA and protein expression and
diminished myocardial function. Therefore, we hypothesize that ischemic loss of m6A eraser, FTO,
increases m6A mRNA methylation resulting in a diminished cardiac function; therefore, FTO gene
transfer may rescue cardiac function in the ischemic hearts (Fig1). Our goal is to unravel the complex
nature of FTO-modulated m6A-epitrancriptome, which plays a critical role in cardiac homeostasis and cardiac
function under ischemia. We propose—for the first time— cardiac epitranscriptome as a highly sensitive,
tunable regulatory layer in the pathomechanism of ischemic cardiomyopathy. The aims are: AIM 1:
Characterize the dynamics of m6A methylation in mRNA and m6A-signature in post-ischemic
mammalian hearts. AIM 2: Determine the role of m6A eraser, FTO in cardiomyocyte and cardiac function.
AIM 3: Investigate the mechanisms of m6A function in cardiac mRNA fate and protein expression at the
molecular and cellular level. Our finding on the dynamic nature of the cardiac epitranscriptome will open up a
new paradigm that will lead to deeper understanding of cardiac remodeling on one hand and innovative
therapeutic interventions on the other.

## Key facts

- **NIH application ID:** 9838295
- **Project number:** 5R01HL140469-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Susmita Sahoo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2018-01-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838295

## Citation

> US National Institutes of Health, RePORTER application 9838295, Dysregulated Adenosine Methylation of mRNA as a Novel Mechanism of Heart Failure (5R01HL140469-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838295. Licensed CC0.

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