# Epigenetic regulation of the metabolic shift in mammalian perinatal hearts

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2024 · $592,363

## Abstract

Abstract: During the transition to extra-uterine life, mammalian hearts undergo a crucial metabolic shift that is
essential for neonatal hearts to adapt to normoxic conditions and the increased cardiac workload experienced
after birth. Proper metabolic transition is essential for establishing normal heart physiology. The long-term goal
of this project is to reveal the molecular and cellular mechanisms that regulate this cardiac metabolic shift using
mouse models and ultimately translate our discoveries into clinical applications addressing inborn
cardiomyopathies.
 Mono-ubiquitination of histone H2A K119 (H2AK119Ub) is a major post-translational modification of
histone H2A, occurring in 5-15% of total H2A in mammalian cells. H2AK119Ub in the promoter region inhibits
RNA polymerase II elongation and acts as a repressive epigenetic mechanism to regulate key developmental
programs from drosophila to mammals. The precise level of H2AK119Ub is dynamically controlled by the balance
between ubiquitin ligases and deubiquitinases. USP16 is a histone H2AK119Ub-specific deubiquitinase that de-
represses gene transcription. To test the role of USP16 in hearts, we specifically deleted Usp16 in the
myocardium. All mutant mice died within 3 days after birth and displayed severe myocardial wall anomalies. Our
subsequent two-hybrid and biochemical analyses revealed that Nuclear Respiratory Factor 1 (NRF1) is a novel
USP16 interaction partner. NRF1 is a nuclear transcription factor that activates expression of the vast majority
of nuclear genes encoding subunits of mitochondrial oxidative phosphorylation (OXPHOS) complexes.
 In support of the functional significance of the USP16-NRF1 interaction, our mRNA-Sequencing analysis
revealed that the pathway involved in OXPHOS was most significantly downregulated by myocardial deletion of
Usp16. We propose our central hypothesis that USP16 interacts with NRF1 to upregulate expression of nuclear
OXPHOS genes, supporting the metabolic shift in perinatal hearts. In Aim 1, we will test how deletion of Usp16
affects the metabolic shift in perinatal hearts. In Aim 2, we will test if OXPHOS genes are major direct regulatory
targets of USP16 in perinatal hearts using high-throughput approaches. In Aim 3, we will test the role of NRF1
in loading USP16 onto its target sites.
 This project will fill a major knowledge gap regarding the basic molecular mechanism underlying the
cardiac metabolic shift, which is critical for the proper transition to extra-uterine life. Our research will contribute
to the development of novel clinical applications aimed at OXPHOS-associated heart defects.

## Key facts

- **NIH application ID:** 10882609
- **Project number:** 1R01HL167945-01A1
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** KAI JIAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $592,363
- **Award type:** 1
- **Project period:** 2024-04-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882609

## Citation

> US National Institutes of Health, RePORTER application 10882609, Epigenetic regulation of the metabolic shift in mammalian perinatal hearts (1R01HL167945-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10882609. Licensed CC0.

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