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NAT10 Is Involved in Cardiac Remodeling Through ac4C-Mediated Transcriptomic Regulation
Jing Shi1, Chuanxi Yang2, Jing Zhang1
1Department of Cardiology (J.S., K.Z., J.Z., P.L., X.W., W.S., X.K.), The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, China.
Circulation Research
|November 13, 2023
Summary
NAT10-mediated N4-acetylcytidine (ac4C) acetylation is elevated in cardiac remodeling. Inhibiting NAT10 reduces cardiac hypertrophy and fibrosis, suggesting ac4C modification as a therapeutic target for heart failure.
Area of Science:
- Molecular Biology
- Epigenetics
- Cardiovascular Research
Background:
- Cardiac remodeling in heart failure involves abnormal epigenetic regulation and gene expression.
- The role of N-acetyltransferase 10 (NAT10) and its associated N4-acetylcytidine (ac4C) modification in cardiac remodeling requires elucidation.
Purpose of the Study:
- To investigate the effects and underlying mechanisms of NAT10-mediated ac4C acetylation in cardiac remodeling.
- To assess the therapeutic potential of targeting NAT10 in cardiac remodeling models.
Main Methods:
- Detection of NAT10 and ac4C expression in human and mouse cardiac remodeling models.
- Utilized next-generation sequencing (RNA-IP-seq, SLAM-seq, Ribo-seq) to analyze ac4C modifications and their impact on RNA.
- Conducted in vivo experiments with NAT10 manipulation and pharmacological inhibition (Remodelin) in mouse models of cardiac stress.
Main Results:
- NAT10 expression and ac4C levels were upregulated in cardiac remodeling, including in patients with hypertrophy.
- NAT10 inhibition attenuated cardiomyocyte hypertrophy and fibroblast activation, improving cardiac function in mice.
- ac4C modifications influenced mRNA stability and translation efficiency of key genes like CD47 and ROCK2.
Conclusions:
- NAT10-mediated ac4C acetylation plays a significant role in cardiac remodeling by regulating gene expression.
- Targeting NAT10 and ac4C epitranscriptomic processes presents a potential therapeutic strategy for heart failure.
