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

• Main Authors: Cai, B. (Author), Chen, W. (Author), Ding, C. (Author), Ge, W. (Author), He, X. (Author), Huang, T. (Author), Li, S. (Author), Liu, J. (Author), Xu, Y. (Author), Xue, M. (Author), Zhang, L. (Author), Zhang, R. (Author), Zhang, Y. (Author), Zhao, T. (Author), Zhao, X. (Author), Zhou, C. (Author)
• Format: Article
• Language: English
• Published: Nature Research 2022
• Online Access: View Fulltext in Publisher

 m5C 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 m5C 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 m5C undergo cell cycle delays and fail to timely initiate maternal-to-zygotic transition, implying the functional importance of maternal mRNA m5C. From invertebrates to the lineage leading to humans, two waves of m5C regulatory innovations are observed: higher animals gain cis-directed NSUN2-mediated m5C 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 m5C 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 m5C in biology and disease. © 2022, The Author(s).