Liu, J., Huang, T., Chen, W., Ding, C., Zhao, T., Zhao, X., Cai, B., Zhang, Y., Li, S., Zhang, L., Xue, M., He, X., Ge, W., Zhou, C., Xu, Y., Zhang, R. (2022). Developmental mRNA m5C landscape and regulatory innovations of massive m5C modification of maternal mRNAs in animals.  Nat. Commun. 13(1): 2484.

FBrf0253409

Research paper

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.

PMC9072368 (PMC) (EuropePMC)