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NAT10-mediated N4-Acetylcytidine is Required for Spermatogenesis and Male Fertility

ABSTRACT: RNA modifications are rapidly emerging as critical post-transcriptional regulators which play a key role in various biological processes. N4-acetylcysteine (ac4C) is one of the “epi-transcriptome” that is present on tRNA, rRNA, mRNA and is also highly conserved in all species. However, cytidine acetylation's in vivo physiological functions remain poorly understood particularly in mammals. Here we demonstrate only known ac4C “writer”—N-acetyltransferase 10 (NAT10) plays essential roles in male reproduction. NAT10 protein and the ac4C modification have different patterns in different organs and there are dynamic changes during spermatogenesis. Germ cell-specific ablation of NAT10 severely inhibited meiotic entry and defects in synapse the homologous chromosomes, repair of DNA double-strand breaks (DSBs) during prophase of the first meiotic division. ac4C RIP-qPCR reveals genes functioning in meiotic prophase I show a decrease in Nat10fl/-; Stra8 GFP-Cre mouse testes. These findings highlight the crucial physiological functions of mRNA ac4C modification in male spermatogenesis and expand our understanding of mRNA ac4C modification in the regulation of specific physiological processes in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE191105 | GEO | 2022/11/16

REPOSITORIES: GEO

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Project description:Background: Heart failure (HF), characterized by cardiac remodeling, is associated with abnormal epigenetic processes and aberrant gene expression. Here, we aimed to elucidate the effects and mechanisms of N-acetyltransferase 10 (NAT10)-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 (acRIP-seq), 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 post-transcriptional regulation in cardiac remodeling. Additionally, functional experiments involving the overexpression or knockdown of NAT10 were conducted in mice models challenged with Ang II and transverse aortic constriction (TAC). 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 cardio-fibroblast 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 TAC 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.

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NAT10-mediated N4-Acetylcytidine is Required for Spermatogenesis and Male Fertility

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