Developmental mRNA m5C landscape and regulatory innovations of massive m5C modification of maternal mRNAs in animals

• Published in: Nature communications Vol. 13; no. 1; pp. 2484 - 13
• Main Authors: Liu, Jianheng, Huang, Tao, Chen, Wanying, Ding, Chenhui, Zhao, Tianxuan, Zhao, Xueni, Cai, Bing, Zhang, Yusen, Li, Song, Zhang, Ling, Xue, Maoguang, He, Xiuju, Ge, Wanzhong, Zhou, Canquan, Xu, Yanwen, Zhang, Rui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.05.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 38/70; 45/91; 5' Untranslated Regions; 631/208/212/748; 631/337/1645/2570; Animals; Cell cycle; Convergence; Developmental stages; Embryogenesis; Embryonic growth stage; Gene mapping; Humanities and Social Sciences; Innovations; Invertebrates; Methylation; mRNA; multidisciplinary; Science; Science (multidisciplinary); Vertebrates
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-30210-0

m 5 C is one of the longest-known RNA modifications, however, its developmental dynamics, functions, and evolution in mRNAs remain largely unknown. Here, we generate quantitative mRNA m 5 C maps at different stages of development in 6 vertebrate and invertebrate species and find convergent and unexpected massive methylation of maternal mRNAs mediated by NSUN2 and NSUN6. Using Drosophila as a model, we reveal that embryos lacking maternal mRNA m 5 C undergo cell cycle delays and fail to timely initiate maternal-to-zygotic transition, implying the functional importance of maternal mRNA m 5 C. From invertebrates to the lineage leading to humans, two waves of m 5 C regulatory innovations are observed: higher animals gain cis-directed NSUN2-mediated m 5 C sites at the 5' end of the mRNAs, accompanied by the emergence of more structured 5'UTR regions; humans gain thousands of trans-directed NSUN6-mediated m 5 C sites enriched in genes regulating the mitotic cell cycle. Collectively, our studies highlight the existence and regulatory innovations of a mechanism of early embryonic development and provide key resources for elucidating the role of mRNA m 5 C in biology and disease. mRNAs are known to be decorated with m5C at a low-to-medium level. Here, the authors generate atlases of mRNA m5C during animal development in 6 species and identify convergent and unexpected massive methylation of maternal mRNAs by NSUN2 and NSUN6.