Maternal N-acetyltransferase 10 (NAT10) orchestrates oocyte meiotic cell-cycle progression and maturation in mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE228721 | GEO | 2023/04/04
REPOSITORIES: GEO
Similar Datasets
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
Project description:Here, we show that NAT10 is an essential regulator of cellular plasticity, and its catalyzed mRNA cytidine acetylation represents a new layer of epitranscriptomic modulation.
2023-11-14 | PXD036888 | Pride
Project description:We show that NAT10-ac4C axis significantly regulates cell fates. To identify the molecular mechanisms of NAT10-ac4C-ANP32B axis in cell-fate transitions, we construct shNAT10 and shANP32B hESCs. acRIP-seq of shCTR and shNAT10 hESCs. We profiled ATAC-seq in shCTR, shNAT10, and shANP32B hESCs. We profiled H3K4me3 and H3K27me3 modifications and the binding of ANP32B by CUT&Tag in shCTR and shNAT10 hESCs.
2023-11-11 | GSE210504 | 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:Zar1 was the first mammalian maternal-effect gene to be identified. Embryos derived from Zar1-null female mice are blocked before zygotic genome activation; however, the underlying mechanism remains unclear. By knocking out Zar1 and its homolog Zar2 in mice, we revealed a novel function of these genes in oocyte meiotic maturation. Zar1/2-deleted oocytes displayed delayed meiotic resumption and polar body-1 emission and a higher incidence of abnormal meiotic spindle formation and chromosome aneuploidy. The grown oocytes of Zar1/2-null mice contained fewer total mRNAs and displayed a reduced level of protein synthesis. Key maturation-associated changes failed to occur in the Zar1/2-null oocytes, including the translational activation of maternal mRNAs encoding the cell cycle proteins cyclin B1 and WEE2, as well as maternal-to-zygotic transition (MZT) licensing factor BTG4. Consequently, maternal mRNA decay was impaired and MZT was abolished. ZAR1/2 bound mRNAs to regulate the translational activity of their 3ʹ-UTRs and interacted with other oocyte proteins, including mRNA-stabilizing protein MSY2 and cytoplasmic lattice components. These results countered the traditional view that ZAR1 only functions after fertilization and highlight a previously unrecognized role of ZAR1/2 in regulating the maternal transcriptome and translational activation in maturing oocytes.
2019-09-25 | GSE135787 | GEO
Project description:In this experiment, we aim to examine the role of NAT10 inhibition in Hutchinson-Gilford progeria syndrome (HGPS), a rare but devastating premature ageing syndrome caused by a mutation in the LMNA gene. NAT10 inhibition improves HGPS cellular phenotypes by releasing Transportin-1 (TNPO1) from the cytoplasm, restoring the TNPO1 pathway and allowing hnRNPA1 and NUP153 nuclear import, TPR anchorage at the nuclear pore complexes and RanGTP gradient re-balancing. We have promoted NAT10 inhibition by two ways in normal or patient derived primary skin fibroblasts; the NAT10 inhibitor Remodelin, and an siRNA directly targeting NAT10 (siNAT10). In addition, we have also used an siRNA against TNPO1 and a combined siTNPO1 and siNAT10 treatment. This is a 2-factor design, with treatment (Remodelin vs untreated, or siNAT10 vs siCT) and condition (HGPS vs normal fibroblasts) as the two conditions. Transcriptional profiling was performed using HumanHT-12 v4 Expression BeadChip microarrays, and all conditions were run in triplicate.
2018-06-25 | E-MTAB-6651 | biostudies-arrayexpress
Project description:Fully grown oocytes remain transcriptionally quiescent, yet many maternal mRNAs are synthesized and retained in growing oocytes. We now know that maternal mRNAs are stored in a structure called the mitochondria associated ribonucleoprotein domain (MARDO). But the components and functions of MARDO remain elusive. Here, we found that LSM14B knockout prevents the proper storage and timely clearance of mRNAs (including Cyclin B1, Btg4, and other mRNAs that are translationally activated during meiotic maturation), specifically by disrupting MARDO assembly during oocyte growth and meiotic maturation. With decreased levels of storage and clearance, the LSM14B knockout oocytes failed to enter meiosis II, ultimately resulting in female infertility. Our results demonstrate the function of LSM14B in MARDO assembly, couple the MARDO with mRNA clearance and oocyte meiotic maturation
2023-10-17 | PXD042761 | Pride
Project description:Targeting NAT10 enhances healthspan and lifespan in a mouse model of human accelerated aging syndrome.
2018-03-22 | E-MTAB-6578 | biostudies-arrayexpress
Project description:Fully grown oocytes remain transcriptionally quiescent, yet many maternal mRNAs are synthesized and retained in growing oocytes. We now know that maternal mRNAs are stored in a structure called the mitochondria associated ribonucleoprotein domain (MARDO). But the components and functions of MARDO remain elusive. Here, we found that LSM14B knockout prevents the proper storage and timely clearance of mRNAs (including Cyclin B1, Btg4, and other mRNAs that are translationally activated during meiotic maturation), specifically by disrupting MARDO assembly during oocyte growth and meiotic maturation. With decreased levels of storage and clearance, the LSM14B knockout oocytes failed to enter meiosis II, ultimately resulting in female infertility. Our results demonstrate the function of LSM14B in MARDO assembly, couple the MARDO with mRNA clearance and oocyte meiotic maturation.
2023-10-15 | GSE231648 | GEO
Project description:We show that non-toxic exogenous palmitate uptake in MCF7 cells promotes NAT10 expression and NAT10-dependent ac4C RNA modification. It was previously reported that NAT10 modulates the addition of ac4C on RNA transcripts in normal and cancer conditions. However, no study report the impact of NAT10 in palmitate driven cells. Here we performed RNA immunoprecipitation sequencing (RIP-seq) in palmitate loaded MCF7 knockdown with NAT10 siRNA. Based on the pathways and enrichment landscape identified. We found that ac4C peaks of fatty acid metabolic genes including ELOVL6, ACSL1, ACSL3, ACSL4, ACADSB and ACAT1 were significantly decreased upon knockdown with NAT10 siRNA. Overall, our results revealed the impact of NAT10 as a regulator of fatty acid metabolism in ac4C-dependent manner
2022-08-03 | GSE210017 | GEO