NAT10 Is Involved in Cardiac Remodeling Through ac4C-Mediated Transcriptomic Regulation

Abstract

Background: Heart failure, characterized by cardiac remodeling, is associated with abnormal epigenetic processes and aberrant gene expression. Here, we aimed to elucidate the effects and mechanisms of NAT10 (N-acetyltransferase 10)-mediated N4-acetylcytidine (ac4C) acetylation during cardiac remodeling. Methods: NAT10 and ac4C expression were detected in both human and mouse subjects with cardiac remodeling through multiple assays. Subsequently, acetylated RNA immunoprecipitation and sequencing, thiol (SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq), and ribosome sequencing (Ribo-seq) were employed to elucidate the role of ac4C-modified posttranscriptional regulation in cardiac remodeling. Additionally, functional experiments involving the overexpression or knockdown of NAT10 were conducted in mice models challenged with Ang II (angiotensin II) and transverse aortic constriction. Results: NAT10 expression and RNA ac4C levels were increased in in vitro and in vivo cardiac remodeling models, as well as in patients with cardiac hypertrophy. Silencing and inhibiting NAT10 attenuated Ang II-induced cardiomyocyte hypertrophy and cardiofibroblast activation. Next-generation sequencing revealed ac4C changes in both mice and humans with cardiac hypertrophy were associated with changes in global mRNA abundance, stability, and translation efficiency. Mechanistically, NAT10 could enhance the stability and translation efficiency of CD47 and ROCK2 transcripts by upregulating their mRNA ac4C modification, thereby resulting in an increase in their protein expression during cardiac remodeling. Furthermore, the administration of Remodelin, a NAT10 inhibitor, has been shown to prevent cardiac functional impairments in mice subjected to transverse aortic constriction by suppressing cardiac fibrosis, hypertrophy, and inflammatory responses, while also regulating the expression levels of CD47 and ROCK2. Conclusions: Therefore, our data suggest that modulating epitranscriptomic processes, such as ac4C acetylation through NAT10, may be a promising therapeutic target against cardiac remodeling.

ac4C: a fragile modification with stabilizing functions in RNA metabolism

“…ac4C RIP-seq has proven invaluable in various cellular studies, confirming ac4C's presence in mRNA and aiding in uncovering its functional roles in diverse pathways including cellular proliferation, cellular development, the DNA damage response, and innate immunity ( Ge et al 2023 ; Jiang et al 2023 ; Liu et al 2023a ; Shi et al 2023 ; Wang et al 2023 ; Xie et al 2023 ). However, this method has its limitations.…”

“…1 ). This enhancement is achieved by improving mRNA stability and translation efficiency ( Arango et al 2018 ; Shi et al 2023 ; Yan et al 2023a ). The exact mechanisms by which ac4C facilitates translation elongation are not fully understood.…”

RNA Modification That Breaks the Heart: RNA Acetylase Nat10 Promotes Fibrosis

“…Considering the housekeeping roles of N6-methyladenosine writers and readers, they are challenging therapeutic targets. 3 Thus, the study by Shi et al 9 not only underpins the relevance of RNA modifications in clinical research but also advocates NAT10 as a promising therapeutic target to treat cardiac remodeling in HF.…”

“…In this issue, Shi et al 9 reports that Nat10 promotes cardiac remodeling using in vivo models of heart failure (HF). Indicative of its potential pathological relevance, they observed elevated NAT10 levels accompanied by a substantial increase in ac 4 C on total RNA in left ventricular tissue derived from patients with myocardial hypertrophy.…”

The positive feedback loop of the NAT10/Mybbp1a/p53 axis promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury

“…NAT10-catalyzed N4-acetylcytidine (ac4C) acetylation of mRNA has been shown to increase mRNA stability and translational efficiency [ 13 ]. Recent studies have reported that NAT10 participates in cardiomyocyte apoptosis and cardiac remodeling in response to different stimuli [ 14 , 15 ]. However, the changes in and role of NAT10 in I/R-induced ferroptosis remain to be determined.…”