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Ac4C-RIP-seq in Control, NAT10 KD, NAT10 and Xrp1 KD in Drosophila

ABSTRACT: In our study, we investigated the role of the ac4C RNA modification enzyme NAT10 in Drosophila development. We found that knockdown of NAT10 led to a global reduction of ac4C levels on rRNA and impaired the assembly of the 40S ribosomal subunit and triggered a ribosome biogenesis stress response. This response was associated with increased cell apoptosis, cell competition, and reduced translational efficiency. Through genetic and transcriptomic analyses, we demonstrated that the developmental defects and transcriptional changes observed upon NAT10 knockdown were largely dependent on the upregulation of Xrp1, a key sensor of ribosome assembly stress. To explore the ac4C epitranscriptomic landscape and its functional implications in mRNA, we performed ac4C-RIP-seq in third instar larvae from three genotypes: Dats-GAL4/+ (control), Dats-GAL4 > UAS-NAT10-RNAi, and Dats-GAL4 > UAS-NAT10-RNAi Xrp1-RNAi. Our results revealed that ac4C modifications were widely distributed across the 5’UTR, CDS, and 3’UTR regions of mRNAs, with relatively higher enrichment in the 3’UTR.Integrated analysis of RNA-seq and ac4C-RIP-seq data revealed that the majority of differentially expressed genes upon NAT10 knockdown were not direct targets of ac4C modification. This indicates that the loss of ac4C on mRNAs has a limited direct impact on the transcriptome. Instead, the observed transcriptional alterations and developmental defects are primarily attributable to ribosome biogenesis stress.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE299446 | GEO | 2026/08/11

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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Ac4C-RIP-seq in Control, NAT10 KD, NAT10 and Xrp1 KD in Drosophila

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