METTL3-mediated m 6 A is required for murine oocyte maturation and maternal-to-zygotic transition

Zhai

et al. 2020

Front. Cell Dev. Biol.

N6-methyladenosine (m 6 A) is one of the most abundant internal mRNA modifications, and it affects multiple biological processes related to eukaryotic mRNA. The majority of m 6 A sites are located in stop codons and 3 UTR regions of mRNAs. m 6 A regulates RNA metabolism, including alternative splicing (AS), alternative polyadenylation (APA), mRNA export, decay, stabilization, and translation. The m 6 A metabolic pathway is regulated by a series of m 6 A writers, erasers and readers. Recent studies indicate that m 6 A is essential for the regulation of gene expression, tumor formation, stem cell fate, gametogenesis, and animal development. In this systematic review, we summarized the recent advances in newly identified m 6 A effectors and the effects of m 6 A on RNA metabolism. Subsequently, we reviewed the functional roles of RNA m 6 A modification in diverse cellular bioprocesses, such as stem cell fate decisions, cell reprogramming and early embryonic development, and we discussed the potential of m 6 A modification to be applied to regenerative medicine, disease treatment, organ transplantation, and animal reproduction.

Section: A Modification and Mammalian Embryonic Developmentmentioning

confidence: 99%

Roles of N6-Methyladenosine (m6A) in Stem Cell Fate Decisions and Early Embryonic Development in Mammals

Zhai

et al. 2020

Front. Cell Dev. Biol.

“…Except for oocyte maturation, RNA m 6 A modi cation has been found to play notable effects on embryonic development [12,38]. In mice, CL exposure resulted in embryos arrested at morula stage [15].…”

Section: Discussionmentioning

confidence: 99%

“…In mammals, m 6 A is regulated by methyltransferase complex (MTC), including methyltransferase like 3 (METTL3), methyltransferase like 14 (METTL14) and Wilms tumor 1associating protein (WTAP). An increasing number of studies indicated that m 6 A play crucial roles in disease development [9], stem cell fate determination [10] and early embryonic development [11,12]. As a major methyl donor in eukaryote, S-adenosylmethionine is synthesised by Methionine adenosyltransferase II (MAT) [13].…”

Section: Introductionmentioning

confidence: 99%

m6a Methylation Inhibition by Cycloleucine Impaired Porcine Oocyte Meiosis and Early Embryonic Development via Remodeling Histone Modifications and Altering Metabolism Related Gene Expression in Blastocysts

Zhang¹,

Zhang²,

Zhai³

et al. 2020

Preprint

BackgroundOocytes maturation and early embryo development were regulated precisely by a series of factors at transcriptional and posttranslational levels. N6-methyladenosine (m6A) is the most prevalent modification in mRNA as a crucial regulator in RNA metabolism and gene regulation. However, the role of m6A on porcine oocyte maturation and early embryogenesis is largely unknown. ResultsHere, we found that oocytes treated with cycloleucine (CL), an inhibitor of m6A, could impair cumulus expansion, elevate mitochondrial reactive oxygen species (ROS) concentration and decreased oocytes maturation which partially caused by disturbed spindle organization and chromosomes alignment. Moreover, our results indicated that the CL treated parthenogenetic embryos arrested at 4-cell stage and showed worse blastocyst quality. CL treatment not only decreased the methylation levels of nucleic acid, H3K4me3 and H3K9me3, while increased the acetylation level of H4K16 during parthenogenetic embryos development in pigs. Furthermore, single cell RNA-seq (scRNA-seq) analysis indicated that CL treatment dramatically elevated the expression of metabolism-related (SLC16A1 and MAIG3 etc.) and maternal related (BTG4, WEE2 and BMP15 etc.) genes at blastocyst stage. ConclusionsTaken together, we found that m6A methylation inhibition by CL impaired porcine oocyte meiosis and early embryonic development via remodeling histone modifications and altering metabolism related gene expression in blastocysts.

“…The m6A modi cation has been demonstrated at the molecular levels to regulate RNA stability, decay, translation, alternative splicing, and exportation [17]. It was recently reported that m6A methylation participated in controlling animal reproduction-associated developmental events, such as spermatogenesis [18,19], oogenesis [20], gamete maturation [21][22][23], oocyte-to-embryo transition [20,24], and blastocyst formation [25]. However, the underlying mechanism on the role of m6A in blastocyst development remains unclear.…”

Section: Introductionmentioning

confidence: 99%

METTL3-mediated m6A methylation negatively modulates autophagy to support blastocyst development

Cao

Hong

et al. 2020

Preprint

Background: N6-methyladenosine (m6A) catalyzed by METTL3 regulates the maternal-to-zygotic transition in zebrafish and mice. However, the role and mechanism of METTL3-mediated m6A methylation in blastocyst development remains unclear. Results: We found that reduced m6A levels triggered by METTL3 knockdown caused embryonic arrest during morula-blastocyst transition and developmental defects in trophectoderm cells. Intriguingly, overexpression of METTL3 in early embryos resulted in increased m6A levels and these embryos phenocopied METTL3 knockdown embryos. Mechanistically, METTL3 knockdown or overexpression resulted in a significant increase or decrease in expression of ATG5 and LC3 (an autophagy marker) in blastocysts, respectively. m6A modification of ATG5 mRNA mainly occurs at 3’UTR, and METTL3 knockdown enhanced ATG5 mRNA stability, suggesting that METTL3 negatively regulated autophagy in an m6A dependent manner. Furthermore, single-cell analysis revealed that METTL3 knockdown only increased expression of LC3 and ATG5 in trophectoderm cells, indicating preferential inhibitory effects of METTL3 on autophagy activity in the trophectoderm lineage. Importantly, autophagy restoration by 3MA (an autophagy inhibitor) treatment partially rescued developmental defects of METTL3 knockdown blastocysts. Conclusions: Our results demonstrate that METTL3-mediated m6A methylation negatively modulates autophagy to support blastocyst development.