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.

中文翻译：

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RNA修饰机制的综合分析揭示了组织和癌症特异性特征

背景 RNA 修饰在细胞命运和分化中起着核心作用。然而，负责放置、去除和识别 170 多种 RNA 修饰的机制在很大程度上仍未得到表征且注释不完善，而且我们目前缺乏确定每种癌症类型中哪些 RNA 修饰相关蛋白 (RMP) 可能失调的综合研究。结果 在这里，我们对人类 RMP 进行了全面的注释和进化分析，并对它们在 32 个组织、10 个物种和 13,358 个配对的肿瘤-正常人类样本中的表达模式进行了综合分析。我们的分析揭示了哺乳动物组织中 RMP 表达模式的意外异质性，大量重复的酶显示睾丸特异性表达，表明 RNA 修饰在精子形成和可能的代际遗传中的关键作用。我们发现许多 RMP 在各种类型的癌症中失调，其表达水平可预测癌症进展。令人惊讶的是，我们发现几种常用的 RNA 修饰酶，如 METTL3 或 FTO，在大多数癌症类型中没有显着上调，而一些不太明确的 RMP，如 LAGE3 和 HENMT1，在许多癌症中失调。结论我们的分析揭示了哺乳动物组织中 RMP 表达模式的意外异质性，并揭示了多种癌症类型中大部分失调的 RMP。我们为未来针对人类表观转录组的癌症研究提供新目标，