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16 February 2021 METTL3-mediated m6A methylation negatively modulates autophagy to support porcine blastocyst development
Zubing Cao, Ling Zhang, Renyun Hong, Yunsheng Li, Yiqing Wang, Xin Qi, Wei Ning, Di Gao, Tengteng Xu, Yangyang Ma, Tong Yu, Jason G Knott, Anucha Sathanawongs, Yunhai Zhang
Author Affiliations +
Abstract

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. Here, we show that METTL3-mediated m6A methylation sustains porcine blastocyst development via negatively modulating autophagy. 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 (a key regulator of autophagy) 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 qPCR 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. Taken together, these results demonstrate that METTL3-mediated m6A methylation negatively modulates autophagy to support blastocyst development.

Summary sentence

METTL3 sustains porcine blastocyst development via inhibiting autophagy.

© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Zubing Cao, Ling Zhang, Renyun Hong, Yunsheng Li, Yiqing Wang, Xin Qi, Wei Ning, Di Gao, Tengteng Xu, Yangyang Ma, Tong Yu, Jason G Knott, Anucha Sathanawongs, and Yunhai Zhang "METTL3-mediated m6A methylation negatively modulates autophagy to support porcine blastocyst development," Biology of Reproduction 104(5), 1008-1021, (16 February 2021). https://doi.org/10.1093/biolre/ioab022
Received: 3 July 2020; Accepted: 10 February 2021; Published: 16 February 2021
KEYWORDS
ATG5
autophagy
blastocyst
m6A methylation
METTL3
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