# Mettl14 mediated mRNA methylation orchestrates postnatal cardiac development

> **NIH NIH R03** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $119,250

## Abstract

The adult mammalian heart has limited capacity for regeneration following injury, but the neonatal mouse
heart possesses remarkable regeneration capacity within 7 days after birth. Defining the molecular mechanisms
that govern regenerative capacity in the neonatal period remains a central goal in cardiac biology. A common
principle observed in tissue regeneration is the reactivation of the previously employed developmental
transcriptional programs. The mechanisms in heart development also govern cardiac regeneration of the injured
heart. Therefore, understanding the transcriptional program regulation during heart development is of critical to
guide cardiac regeneration therapies. Inducible pluripotent stem cell (iPSC) derived cardiomyocyte has been
developed for disease research and drug development, and these cells are now gradually entering the clinical
research phase for the testing of heart regeneration therapies. However, a major hurdle for their applications is
the immature state of these cardiomyocytes.Cardiac development is orchestrated by multiple layers of
epigenetic regulation in a collaborative and strictly temporal manner. New high-throughput sequencing
approaches have begun to reveal a new layer of epigenetic regulation, mRNA methylation (N6-methyladenosine,
m6A). The m6A is installed by the methyltransferase complex consisting of methyltransferase-like 3 (Mettl3)
and Mettl14. The recent discovery of the broad role of m6A mRNA methylation in regulating cell fates, embryonic
and brain development, and stress response in adult brain highlights the importance of another layer of
epigenetic regulation at the RNA level. Conditional Mettl14 knockout in nerves system resulted in abnormal brain
development and early death after birth. Delayed differentiation/maturation due to prolonged cell cycle or
impaired neuron proliferation are two possible underlying mechanisms. The role of m6a mRNA methylation in
cardiac development is still largely unknown. Cardiac-specific Mettl3 knockout mice showed no evident heart
development deficiency. However, we discovered that cardiac-specific Mettl14 KO mice (cMettl14 KO) displayed
severe cardiomyopathy resulting death within two months after birth. The mechanisms of the cardiomyopathy in
cMettl14 KO mice are unclear. We performed m6A sequencing on the hearts from WT and cMettl14 KO mice at
the age of 5 days. We found that many of the decreased m6A tagged transcripts in cMettl14 KO mice were
related to cardiomyocyte differentiation, proliferation, maturation or hypertrophy. Among them, the m6A level and
mRNA level of Bone Morphogenic protein 2 (BMP2), BMP10 and Wingless-Type MMTV Integration Site Family,
Member 5A (WNT5a) were significantly decreased in cMettle14 KO mice. Importantly, we found that the
proliferation of cardiomyocyte was increased in cMettl14 KO mice, while the maturation of the cardiomyocyte,
assessed by calcium transient, mitochondrial function and the level of fetal/adult myofilament iso...

## Key facts

- **NIH application ID:** 10950644
- **Project number:** 1R03HL174881-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Manling Zhang
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $119,250
- **Award type:** 1
- **Project period:** 2024-08-26 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10950644

## Citation

> US National Institutes of Health, RePORTER application 10950644, Mettl14 mediated mRNA methylation orchestrates postnatal cardiac development (1R03HL174881-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10950644. Licensed CC0.

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