Integrative analyses of the RNA modification machinery reveal tissue- and cancer-specific signatures.
BACKGROUND
RNA modifications play central roles in cellular fate and differentiation. However, the machinery responsible for placing, removing, and recognizing more than 170 RNA modifications remains largely uncharacterized and poorly annotated, and we currently lack integrative studies that identify which RNA modification-related proteins (RMPs) may be dysregulated in each cancer type.


RESULTS
Here, we perform a comprehensive annotation and evolutionary analysis of human RMPs, as well as an integrative analysis of their expression patterns across 32 tissues, 10 species, and 13,358 paired tumor-normal human samples. Our analysis reveals an unanticipated heterogeneity of RMP expression patterns across mammalian tissues, with a vast proportion of duplicated enzymes displaying testis-specific expression, suggesting a key role for RNA modifications in sperm formation and possibly intergenerational inheritance. We uncover many RMPs that are dysregulated in various types of cancer, and whose expression levels are predictive of cancer progression. Surprisingly, we find that several commonly studied RNA modification enzymes such as METTL3 or FTO are not significantly upregulated in most cancer types, whereas several less-characterized RMPs, such as LAGE3 and HENMT1, are dysregulated in many cancers.


CONCLUSIONS
Our analyses reveal an unanticipated heterogeneity in the expression patterns of RMPs across mammalian tissues and uncover a large proportion of dysregulated RMPs in multiple cancer types. We provide novel targets for future cancer research studies targeting the human epitranscriptome, as well as foundations to understand cell type-specific behaviors that are orchestrated by RNA modifications.
['Begik|Oguzhan|O|', 'Lucas|Morghan C|MC|', 'Liu|Huanle|H|', 'Ramirez|Jose Miguel|JM|', 'Mattick|John S|JS|', 'Novoa|Eva Maria|EM|']
D000818:Animals D002352:Carrier Proteins D004822:Epididymis D019143:Evolution, Molecular D006801:Humans D008297:Male D008540:Meiosis D008780:Methyltransferases D051379:Mice D058977:Molecular Sequence Annotation D009369:Neoplasms D009928:Organ Specificity D012323:RNA Processing, Post-Transcriptional D013091:Spermatogenesis
RNA modifications Epitranscriptomics Dysregulation in cancer Tissue specificity