Source: School of Life Sciences
Written by: School of Life Sciences
Edited by: Wang Dongmei

Recently, Prof. Rui Zhang’s group at School of Life Sciences, Sun Yat-sen University, published a research article titled “Genome-wide identification of mRNA 5-methylcytosine in mammals” in Nature Structural & Molecular Biology. This article reported a method for accurate identification of m5C methylation in mRNAs. It also uncovered that mRNA m5C has a unique sequence context and structural feature. Prof. Rui Zhang is the corresponding author. Tao Huang (distinguished associate researcher), Wanying Chen (PhD student) and Jianheng Liu (PhD student) are the co-first authors. This study is funded by the National Key R&D Program of China, Guangdong Major Science and Technology Projects, Guangdong Innovative and Entrepreneurial Research Team Program and National Natural Science Foundation of China.

5-methylcytosine (m5C) is an RNA modification that broadly exists on tRNA and rRNA, however, it is still controversial if mRNA contains m5C modification. Through the analysis, this study found that most of the previously reported “m5C” sites were clustered in GC-rich regions, insensitive to NSUN2 knock down, and cannot be enriched by anti-m5C antibodies, which together indicate these sites may be false positives. Based on these findings, this study developed a novel computational method to robustly identify high-confidence mRNA m5C sites. Further analysis shows that NSUN2-dependent m5C sites tend to have a 3’ G-rich motif, which locates at the 5’end of a stem-loop structure. This feature resembles the feature of NSUN2 tRNA substrates. A quantitative atlas of mRNA m5C sites in human and mouse tissues was further developed based on the computational method. In a given tissue, several hundred exonic m5C sites were identified. Cross-species analysis revealed that species, rather than tissue type, was the primary determinant of methylation levels, indicating strong cis-directed regulation of m5C methylation.

Taken as a whole, this study establishes a new method for mRNA m5C discovery; the quantitative atlas of mammalian mRNA m5C it developed provides a valuable resource for identifying the regulation and functions of RNA methylation. Prof. Alexandra Lusser from Medizinische Universität Innsbruck commented that this study increases the accuracy in m5C identification and provides intriguing evidence of a role for NSUN2 in the methylation of mRNA.

Links:
https://www.nature.com/articles/s41594-019-0218-x
https://www.nature.com/articles/s41594-019-0217-y