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Transcriptomic ac4C profiling in NAT10 knockdown acute myeloid leukemia cells

ABSTRACT: RNA modification represents an important post-transcriptional regulatory mechanism in acute myeloid leukemia (AML), however the function and mechanism of RNA acetylation ac4C in AML remains elusive. Here, we report that NAT10, as the ac4C writing enzyme, plays a critical oncogenic function in AML and represents a promising therapeutic target for AML. To understand the mechanisms underlying the function of NAT10 as an RNA ac4C writer in AML, we profiled ac4C modification in the transcriptome of MOLM13 cells using a refined ac4C RNA immunoprecipitation and high throughput sequencing (RacRIP-seq) protocol, and performed systematic calibration with a modification-free control library generated from the in vitro- transcribed MOLM13 transcriptome (referred to as IVT control) to eliminate most of the false- positive signals. We also applied the RacRIP-seq in NAT10 knockdown and control MOLM13 cells to characterize NAT10 targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246505 | GEO | 2024/08/26

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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Transcriptomic ac4C profiling in NAT10 knockdown acute myeloid leukemia cells

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