Integrative analyses of the RNA modification machinery reveal tissue- and cancer-specific signatures
Integrative analyses of the RNA modification machinery reveal tissue- and cancer-specific signatures
复制标题
DOI：
10.1186/s13059-020-02009-z
复制
发表时间：
2020-05-07
期刊：
影响因子：
12.3
通讯作者：
Maria Novoa, Eva
中科院分区：
文献类型：
--
作者：
Begik, Oguzhan;Lucas, Morghan C.;Maria Novoa, Eva
RNA修饰在细胞命运和分化中起着核心作用。然而，负责放置、去除和识别超过170种RNA修饰的机制在很大程度上仍未被表征和注释，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。在这里，我们对人类RMPs进行了全面的注释和进化分析，并对32个组织、10个物种和13358对肿瘤-正常人类样本中的RMPs表达模式进行了综合分析。我们的分析揭示了RMP在哺乳动物组织中的表达模式出乎意料的异质性，大量重复的酶显示睾丸特异性表达，这表明RNA修饰在精子形成和可能的代际遗传中起关键作用。我们发现许多RMPs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，我们发现一些常见的RNA修饰酶，如METTL3或FTO，在大多数癌症类型中并没有显著上调，而一些较少表征的RMPs，如LAGE3和HENMT1，在许多癌症中都是失调的。我们的分析揭示了RMPs在哺乳动物组织中表达模式的意想不到的异质性，并揭示了多种癌症类型中大量失调的RMPs。我们为未来针对人类表转录组的癌症研究提供了新的靶点，也为理解由RNA修饰策划的细胞类型特异性行为奠定了基础。
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.