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The RNA ac4C Writer NAT10-dependent Post-transcriptional Regulations are Prerequisites for Zygotic Splicing Activation in Mouse [RNA-Seq]

ABSTRACT: Programmed establishment of the zygote epitranscriptome orchestrates epitranscriptome fidelity and developmental potency acquisition during mammalian preimplantation embryogenesis. N4-acetylcytidine (ac4C) is a conserved post-transcriptional RNA modification catalyzed by the only known “writer”, N-acetyltransferase 10 (NAT10), but its landscape and function in early embryos remain further exploration owing to limited materials. In this study, we characterized the ac4C modification reprogramming dynamics throughout preimplantation embryogenesis and identified that Nat10 ablation from primary follicle oocytes leads to female infertility with embryonic arrest at the 2-cell transition. Notably, we found that the maternal protein NAT10 was essential for ac4C deposition on ZGA transcripts and maternal mRNAs, and the loss of Nat10 could also lead to abnormal accumulation of maternal transcripts and major ZGA inactivation. Interestingly, through combinatorial interrogation of RNA-seq and ribo-seq data, we uncovered NAT10 regulates the alternative splicing of transcripts that function during zygotic splicing activation in an ac4C-dependent manner. In summary, our findings demonstrate that the RNA ac4C writer NAT10 is essential for the post-transcriptional regulation of mouse zygotic splicing activation and provide valuable view for further exploration of the epigenetic mechanism during maternal-to-zygotic transition.

ORGANISM(S): Mus musculus

PROVIDER: GSE308580 | GEO | 2026/08/11

REPOSITORIES: GEO

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The RNA ac4C Writer NAT10-dependent Post-transcriptional Regulations are Prerequisites for Zygotic Splicing Activation in Mouse

Project description:Programmed establishment of the zygote epitranscriptome orchestrates epitranscriptome fidelity and developmental potency acquisition during mammalian preimplantation embryogenesis. N4-acetylcytidine (ac4C) is a conserved post-transcriptional RNA modification catalyzed by the only known “writer”, N-acetyltransferase 10 (NAT10), but its landscape and function in early embryos remain further exploration owing to limited materials. In this study, we characterized the ac4C modification reprogramming dynamics throughout preimplantation embryogenesis and identified that Nat10 ablation from primary follicle oocytes leads to female infertility with embryonic arrest at the 2-cell transition. Notably, we found that the maternal protein NAT10 was essential for ac4C deposition on ZGA transcripts and maternal mRNAs, and the loss of Nat10 could also lead to abnormal accumulation of maternal transcripts and major ZGA inactivation. Interestingly, through combinatorial interrogation of RNA-seq and ribo-seq data, we uncovered NAT10 regulates the alternative splicing of transcripts that function during zygotic splicing activation in an ac4C-dependent manner. In summary, our findings demonstrate that the RNA ac4C writer NAT10 is essential for the post-transcriptional regulation of mouse zygotic splicing activation and provide valuable view for further exploration of the epigenetic mechanism during maternal-to-zygotic transition.

2026-08-11 | GSE308284 | GEO

PCBP1/2 and TDP43 Function As NAT10 Adaptors In ac4C Writer Complex Towards mRNAs in Mammalian Cells [293T_acRIPseq]

Project description:Massive numbers of modified bases in mRNAs sculpt the epitranscriptome and play vital roles in RNA metabolism. The only known acetylated RNA modification, N-4-acetylcytidine (ac4C), is highly conserved across cell types and among species. Although the GCN5-related acetyltransferase 10 (NAT10) functions as an ac4C writer, the mechanism underlying the acetylation process is largely unknown. In this study, we identified the NAT10/PCBP/TDP43 complex as an mRNA ac4C writer in mammalian cells. We identified RNA-binding proteins (RBPs) affiliated with two different families, PCBP1/2 (poly(rC)-binding protein 1/2) and TDP43 (TAR DNA binding protein 43), as NAT10 adaptors for mRNA tethering and substrate selection. Knockdown of the adaptors resulted in decreased mRNA acetylation abundance in HEK293T cells, with globally reduced density in 5`-untranslated region (UTR) and coding sequence (CDS) and ablated cytidine-rich ac4C motifs. The adaptors also affect the ac4C sites by recruiting NAT10 to their binding sequences. The presence of the NAT10/PCBP/TDP43 complex in mouse testes highlights its potential physiological functions in vivo. These findings reveal the composition of the mRNA ac4C writer complex in mammalian cells and expand our knowledge of mRNA acetylation and ac4C site preferences.

2024-12-27 | GSE252076 | GEO

PCBP1/2 and TDP43 Function As NAT10 Adaptors In ac4C Writer Complex Towards mRNAs in Mammalian Cells [acRIPseq]

2024-12-27 | GSE252075 | GEO

DPPA2 and DPPA4 are dispensable for mouse zygotic genome activation and preimplantation development

Project description:How maternal factors in oocytes initiate zygotic genome activation (ZGA) remains elusive. Recent studies indicate that DPPA2 and DPPA4 are required for establishing a 2-cell embryo-like (2C-like) state in mouse embryonic stem cells (ESCs) in a DUX-dependent manner. These results suggest that DPPA2 and DPPA4 are essential maternal factors that regulate Dux and ZGA in embryos. By analyzing maternal knockout and maternal-zygotic knockout embryos, we unexpectedly found that Dux activation, ZGA, and preimplantation development are normal in embryos without DPPA2 or DPPA4. Thus, unlike in ESCs/2C-like cells, DPPA2 and DPPA4 are dispensable for ZGA and preimplantation development.

2021-12-06 | GSE181723 | GEO

NAT10-mediated mRNA N4-acetylcytidine is Essential for the Translational Regulation of Oocyte Meiotic Maturation in Mice

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

NAT10-mediated mRNA N4-acetylation is Essential for the Translational Regulation During Oocyte Meiotic Maturation in Mice

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

NAT10-mediated mRNA N4-acetylcytidine Modifications in Mouse Oocytes Constitute a Checkpoint of Ovarian Follicle Development [RIP-Seq]

Project description:During mammalian follicular development, the correct establishment of the epitranscriptome in oocytes is essential for precise gene repression and the acquisition of developmental competence. N4-acetylcytidine (ac4C) is a conserved posttranscriptional RNA modification catalyzed by the only known “writer”, N-acetyltransferase 10 (NAT10). NAT10-targeted transcripts in oocytes and their functions in supporting folliculogenesis are poorly understood. In this study, we showed that oocyte-specific knockout of Nat10 resulted in retardation of oocyte growth with defective follicular development, premature ovarian failure, and female sterility. We profiled the ac4C landscape in the ovarian transcriptome and identified many folliculogenesis-related oocyte genes with ac4C modifications. Loss of Nat10 in oocytes eliminated ac4C signals, resulting in the downregulation of numerous oocyte-derived transcripts with reduced stability. Moreover, Nat10-deletion in oocytes or mutations in these ac4C sites led to decreased levels of protein translation, whereas the introduction of ac4C into these mRNAs increased their translational efficiencies. In addition, our data showed that the distinct gene expression patterns in granulosa cells within arrested secondary follicles were disrupted, and the identity of granulosa cells was altered by Nat10 deletion in oocytes. Taken together, these findings provide evidence that NAT10-mediated ac4C modification is a crucial regulatory factor in the maintenance of oocyte competence and that it constitutes a checkpoint for ovarian folliculogenesis beyond the secondary follicle stage.

2026-05-04 | GSE266987 | GEO

NAT10-mediated mRNA N4-acetylcytidine Modifications in Mouse Oocytes Constitute a Checkpoint of Ovarian Follicle Development [NAT10-smart-seq2]

2026-05-04 | GSE266989 | GEO

Quantitative proteomics analysis of acute myeloid leukemia cells after NAT10 knockdown

Project description:RNA modification represents an important post-transcriptional regulatory mechanism in acute myeloid leukemia (AML). Given that the critical function of ac4C in control RNA translation, we sought to investigate the global impact of ac4C on protein expression. To this end, we conducted tandem mass tag (TMT) labeling and quantitative proteomics in MOLM13 AML cells with or without the ac4c writer NAT10 silencing.

2024-08-26 | PXD055119 | Pride

Dynamic RNA-protein interactions underlie the zebrafish maternal-to-zygotic transition

Project description:During the maternal-to-zygotic transition (MZT), transcriptionally silent embryos rely on post-transcriptional regulation of maternal mRNAs until zygotic genome activation (ZGA). RNA-binding proteins (RBPs) are important regulators of post-transcriptional RNA processing events, yet their identities and functions during developmental transitions in vertebrates remain largely unexplored. Using mRNA interactome capture, we identified 227 RBPs in zebrafish embryos before and during ZGA, hereby named the zebrafish MZT mRNAbound proteome. This protein constellation consists of many conserved RBPs, with additional embryo- and stage-specific mRNA interactors that likely reflect the dynamics of RNA-protein interactions during MZT. The enrichment of numerous splicing factors like hnRNP proteins before ZGA was surprising, because maternal mRNAs were found to be fully spliced. To address potentially unique roles of RBPs in embryogenesis, we focused on hnRNP A1. iCLIP and subsequent mRNA reporter assays revealed a function for hnRNP A1 in the regulation of poly(A) tail length and translation of maternal mRNAs through sequence-specific association with 3’UTRs before ZGA. Comparison of iCLIP data from two developmental stages revealed that hnRNP A1 dissociates from maternal mRNAs at ZGA and instead regulates the nuclear processing of pri-miR-430 transcripts, which we validated experimentally. The shift from cytoplasmic to nuclear RNA targets was accompanied by a dramatic translocation of hnRNP A1 and other pre-mRNA splicing factors to the nucleus in a transcription-dependent manner. Thus, our study identifies global changes in RNA-protein interactions during vertebrate MZT and shows that hnRNP A1 RNA-binding activities are spatially and temporally coordinated to regulate RNA metabolism during early development.

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