NAT10-mediated mRNA N4-acetylcitidine (ac4C) Promotes Stemness and Leukemogenesis in Acute Myeloid Leukemia
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ABSTRACT:
PROVIDER: PRJNA1033527 | ENA |
REPOSITORIES: ENA
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Project description:N4-acetylcytidine (ac4C), a conserved chemical modification in eukaryotic prokaryotes that is catalyzed by the N-acetyltransferase 10 (NAT10) enzyme, plays a crucial role in promoting mRNA stability and translation. However, the biological function and mechanisms of NAT10-mediated ac4C in human cancer were poorly defined. In order to investigate the regulatory mechanism of NAT10 in gastric cancer, we performed ac4C RIP-seq(acRIP-seq) analysis in AGS cells with NAT10 knockout compared with control in two repeats.
2024-07-07 | GSE180494 | GEO
Project description:NAT10-catalyzed N4-acetylcytidine (ac4C) has emerged as a vital post-transcriptional modulator on the coding transcriptome by promoting mRNA stability. To explore the transcriptome-wide profile of ac4C modification, we mapped the locations of ac4C modification on wild-type (WT) hESCs and NAT10 KD hESCs by NaCNBH3-based chemical ac4C sequencing (ac4C-seq).
2023-08-25 | GSE226747 | GEO
Project description:N4-acetylcytidine (ac4C), a newly identified epigenetic modification within mRNAs, has been characterized as a crucial regulator of mRNA stability and translation efficiency. And NAT10 is the only known RNA acetyltransferase. In our study, we documented the down-regulated expression of both ac4C and NAT10 during meiotic maturation of mouse oocytes. NAT10 knockdown resulted in ac4C reduction and impaired mouse oocyte maturation in vitro. These results indicated that NAT10-mediated ac4C modification plays a critical regulatory role in oocyte meiotic maturation. We further performed high-throughput sequencing with NAT10-overexpressed HEK293T cells and NAT10-binding transcripts to investigate the genes modulated by NAT10-mediated ac4C modification.
2021-07-11 | GSE179429 | GEO
Project description:NAT10-catalyzed N4-acetylcytidine (ac4C) has emerged as a vital post-transcriptional modulator on the coding transcriptome by promoting mRNA stability. To explore the transcriptome-wide profile of ac4C modification, we mapped the locations of ac4C modification on wild-type (WT) hESCs and NAT10 KD hESCs by high-throughput ac4C RNA immunoprecipitation sequencing (ac4C-RIP-seq).
2023-08-25 | GSE226748 | GEO
Project description: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.
2022-11-16 | GSE191105 | GEO
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.
2023-10-31 | GSE233736 | GEO
Project description:Despite the advance in diagnosis and treatment, the prognosis of osteosarcoma patients remains unsatisfied. Therefore, it is imperative to identify novel therapeutic targets for osteosarcoma. Through RNA sequencing (RNA-seq) combined with functional screening, N4-acetylcytidine (ac4C) acetyltransferase 10 (NAT10) was identified as a candidate therapeutic target in osteosarcoma. Upregulated NAT10 correlated with poor prognosis in osteosarcoma patients and NAT10 knockout drastically inhibited cell proliferation and metastasis in vitro and in vivo. NAT10 enhanced mRNA stability and translation efficiency of activating transcription factor 4 (ATF4) through ac4C modification. ATF4 induced transcription of asparagine synthetase (ASNS), which catalyzes asparagine (Asn) biosynthesis. Asn promote protein and nucleotide synthesis, facilitating osteosarcoma progression. Overexpression of ATF4, ASNS or supplementation of asparagine rescue the tumor inhibitory effect of NAT10 knockout.
2024-08-09 | GSE237840 | GEO
Project description:Despite the advance in diagnosis and treatment, the prognosis of osteosarcoma patients remains unsatisfied. Therefore, it is imperative to identify novel therapeutic targets for osteosarcoma. Through RNA sequencing (RNA-seq) combined with functional screening, N4-acetylcytidine (ac4C) acetyltransferase 10 (NAT10) was identified as a candidate therapeutic target in osteosarcoma. Upregulated NAT10 correlated with poor prognosis in osteosarcoma patients and NAT10 knockout drastically inhibited cell proliferation and metastasis in vitro and in vivo. NAT10 enhanced mRNA stability and translation efficiency of activating transcription factor 4 (ATF4) through ac4C modification. ATF4 induced transcription of asparagine synthetase (ASNS), which catalyzes asparagine (Asn) biosynthesis. Asn promote protein and nucleotide synthesis, facilitating osteosarcoma progression. Overexpression of ATF4, ASNS or supplementation of asparagine rescue the tumor inhibitory effect of NAT10 knockout.
2024-08-09 | GSE237541 | GEO
Project description:Mammalian oocyte maturation is driven by strictly translational regulation of maternal mRNAs stored in the cytoplasm. However, the function and mechanism of post-transcriptional chemical modifications especially the newly identified N4-acetylcytidine (ac4C) catalyzed by N-acetyltransferase 10 (NAT10) in this process are previously unknown. In this study, we developed a low-input ac4C sequencing technology - ac4C LACE-seq and mapped 8241 ac4C peaks at the whole transcriptome level using 50 mouse oocytes at the germinal vesicle (GV) stage. We profiled the mRNA landscapes of NAT10-interactions and ac4C modifications. The NAT10-interacted and ac4C modified transcripts displayed association with high translation efficiency in oocytes. Oocyte-specific Nat10 knockout wiped out ac4C signals in oocytes and caused severe defects in meiotic maturation and female infertility. ac4C LACE-seq results indicated that Nat10 deletion led to a failure of ac4C deposition on mRNAs encoding key maternal factors such as MAY2, ZAR1, BTG4 and cyclin B1 that regulate transcriptome stability and maternal-to-zygotic transition. Nat10-deleted oocytes had decreased mRNA translation efficiencies during meiotic maturation, partially due to the direct inhibition ac4C sites on specific transcripts. In sum, we developed low-input, high-sensitivity mRNA ac4C profiling approach and highlighted the important physiological function of ac4C in precise regulation of the oocyte meiotic maturation by enhancing translation efficiency.
2024-08-26 | GSE253976 | GEO
Project description:Mammalian oocyte maturation is driven by strictly translational regulation of maternal mRNAs stored in the cytoplasm. However, the function and mechanism of post-transcriptional chemical modifications especially the newly identified N4-acetylcytidine (ac4C) catalyzed by N-acetyltransferase 10 (NAT10) in this process are previously unknown. In this study, we developed a low-input ac4C sequencing technology—ac4C LACE-seq and mapped 8241 ac4C peaks at the whole transcriptome level using 50 mouse oocytes at the germinal vesicle (GV) stage. We profiled the mRNA landscapes of NAT10-interactions and ac4C modifications. The NAT10-interacted and ac4C modified transcripts displayed association with high translation efficiency in oocytes. Oocyte-specific Nat10 knockout wiped out ac4C signals in oocytes and caused severe defects in meiotic maturation and female infertility. ac4C LACE-seq results indicated that Nat10 deletion led to a failure of ac4C deposition on mRNAs encoding key maternal factors such as MAY2, ZAR1, BTG4 and cyclin B1 that regulate transcriptome stability and maternal-to-zygotic transition. Nat10-deleted oocytes had decreased mRNA translation efficiencies during meiotic maturation, partially due to the direct inhibition ac4C sites on specific transcripts. In sum, we developed low-input, high-sensitivity mRNA ac4C profiling approach and highlighted the important physiological function of ac4C in precise regulation of the oocyte meiotic maturation by enhancing translation efficiency.
2024-02-18 | GSE254288 | GEO