Cap-specific second nucleotide ribose methylase CMTR2 is required for transcriptome transition during mammalian germline development

Eukaryotic RNA polymerase II transcripts carry a signature m7G cap (Cap0) structure that is co-transcriptionally added to the 5 end, and is essential for translation and RNA stability. Higher eukaryotes carry additional essential ribose methylations on the first and second cap-proximal nucleotides, termed as Cap1 and Cap2, respectively. The ubiquitous Cap1 modification protects cellular RNAs from being recognized by the innate immune sensors. Cap2 is also implicated in such an innate immune role, but here we use our genetic analyses of two human cell lines and three mouse tissues to reveal that loss of CMTR2 does not result in activation of the innate immune response. Germline deletion of mouse CMTR2 shows that it is required for male and female fertility. While mutant germ cells proceed into the meiotic pachytene spermatocyte stage, their transcriptome fails to keep pace and transition from the preceding leptotene/zygotene stages. Such a meiotic role is not conserved in other vertebrates like zebrafish, as cmtr2 mutants are fertile, instead it has a role in defining sex, as all mutants are exclusively males. Taken together, our study reveals that CMTR2 does not influence innate immune response in human cells and mouse tissues, but shapes gene expression during developmental transitions.