# YTHDF3 as a critical regulator of cardiac function

> **NIH NIH F30** · OHIO STATE UNIVERSITY · 2024 · $44,224

## Abstract

PROJECT SUMMARY
As the global leading cause of death, heart failure is a major challenge for researchers in their quest to discover
therapeutics that can save countless lives. After cardiac injury, the heart begins to remodel itself in a way that is
initially adaptive, but this innate coping mechanism may over time expedite heart failure onset. Elucidating the
mechanisms which underly the progression from adaptive cardiac hypertrophic remodeling to heart failure will
dramatically impact the discovery of novel therapeutics for this deadly disease. While regulation of gene
expression through transcription of messenger RNA (mRNA) has been extensively studied, only recently an
appreciation for the importance of chemical modifications that can occur on mRNA has emerged. This proposal
focuses on the methylation of the N6-Adenosine of mRNA (m6A), which is the most abundant internal mRNA
modification in eukaryotes. Previous research from our lab has shown that modulation of m6A content in the
heart is sufficient to drive cardiac remodeling and to affect the ability of the heart to respond to stress. Despite
this, the exact mechanisms through which this occurs is not well understood. The fate of m6A-modified mRNAs
is regulated by members of the YTH Domain Family (YTHDF). We found that YTHDF3 is specifically important
in cardiomyocytes, where it localizes to the nucleus and binds to Myocyte Enhancer Factor 2D (MEF2D), which
is an important transcription factor regulating hypertrophic cardiac growth. Further, we have found that knockout
of YTHDF3 mitigates pathological remodeling following pressure overload injury. Given these preliminary data,
we hypothesize that YTHDF3 regulates cardiomyocyte size and stress-induced remodeling by modulating
the processing of m6A-modified mRNAs transcribed by MEF2D. To test this hypothesis, we already
generated and validated a new mouse line in which YTHDF3 can be selectively deleted in cardiomyocytes
(YTHDF3-cKO). In Aim 1, we will investigate the role of YTHDF3 at baseline and in the stressed murine heart
using longitudinal echocardiography analysis, and assessing histological and molecular signs of pathology at
the terminal time point. In Aim 2, we will determine the mechanism through which YTHDF3 regulates the fate of
specific subsets of MEF2D-transcribed m6A-mRNAs in cardiomyocytes. First, we will further characterize the
binding between YTHDF3 and MEF2D by defining the respective domains involved. Then, we will dissect the
binding of YTHDF3 to MEF2D mRNA targets and determine consequent stability, export, and translation of these
transcripts. Finally, in Aim 3, we will undertake an unbiased approach to more globally investigate the role of
YTHDF3 in regulating mRNA biology in healthy and stressed adult cardiomyocytes by cross-linking
immunoprecipitations of YTHDF3-bound mRNAs followed by sequencing (CLIP-seq). Our approach is innovative
and significant, as it will be the first project to define the role of YTHDF3 in ...

## Key facts

- **NIH application ID:** 10898620
- **Project number:** 5F30HL165812-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Charles P. Rabolli
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $44,224
- **Award type:** 5
- **Project period:** 2023-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898620

## Citation

> US National Institutes of Health, RePORTER application 10898620, YTHDF3 as a critical regulator of cardiac function (5F30HL165812-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10898620. Licensed CC0.

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