Abstract
BackgroundRNA 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.ResultsHere, 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.ConclusionsOur 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.
Highlights
RNA modifications play central roles in cellular fate and differentiation
To determine the evolutionary history and identify duplication events that occurred in each family, ortholog proteins from representative species were retrieved, and phylogenetic trees were built to identify the number of duplications occurring within each family
We find that the majority of RNA modificationrelated proteins (RMPs), including those involved in placing, reading, and removing m6A (VIRMA, YTHDC2, YTHDF2, alkB homolog 5 (ALKBH5), METTL14, METTL3) are highly expressed in spermatogonial cells, whereas their expression rapidly drops as the spermatogenic process begins (Fig. 3b, c, see Additional file 13: Figure S6C)
Summary
RNA modifications play central roles in cellular fate and differentiation. 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 modificationrelated proteins (RMPs) may be dysregulated in each cancer type. A number of studies have shown that RNA modifications can profoundly affect central biological processes, including cell fate [7], sex determination [8, 9], maternal-tozygotic transition [10], and the circadian clock [11] as well as plant developmental timing, morphogenesis, and flowering [12]. Dysregulation of their activity has been associated with more than 100 different human diseases [13,14,15,16,17]. The functional characterization of the majority of RNA modifications still remains an uncharted territory
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