Integrative analyses of the RNA modification machinery reveal tissue- and cancer-specific signatures

Begik, Oguzhan; Lucas, Morghan C.; Liu, Huanle; Ramírez, José Miguel; Mattick, John S.; Novoa, Eva María

doi:10.1101/830968

Cited by 19 publications

(25 citation statements)

References 90 publications

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“…All scripts used in this work have been made publicly available and can be found at https://github.com/novoalab/ RNAModMachinery [101]. All datasets used to build the figures, as well as intermediate analysis files (alignment files, maximum likelihood trees, scatter plots of tissue specificity, barplots of amniote and primate ortholog expressions, scatter plots of tumor vs normal tissues, boxplots of individual expression of RMPs in tumor-normal paired tissues and survival plots), are publicly available at https://public-docs.crg.es/enovoa/public/website/Begik_RMP2020.html.…”

Section: Supplementary Informationmentioning

confidence: 99%

Integrative analyses of the RNA modification machinery reveal tissue- and cancer-specific signatures

et al. 2020

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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 modificationrelated 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 testisspecific 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.

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Section: Supplementary Informationmentioning

confidence: 99%

Integrative analyses of the RNA modification machinery reveal tissue- and cancer-specific signatures

et al. 2020

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“…They have mostly been characterised as either targeting tRNA (NSUN2, 3, and 6; TRDMT1) or rRNA (NSUN1, 4, and 5) [21,40]. Despite their seemingly 'housekeeping' functions, these MTases display complex expression patterns during development and disease, especially in cancer, and mutations in several of them cause human genetic disease [40][41][42][43]. One explanation for their complex biology might be that these MTases modify additional substrates outside of the tRNA and rRNA realm.…”

Section: Introductionmentioning

confidence: 99%

Multiple links between 5-methylcytosine content of mRNA and translation

et al. 2020

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Background: 5-Methylcytosine (m 5 C) is a prevalent base modification in tRNA and rRNA but it also occurs more broadly in the transcriptome, including in mRNA, where it serves incompletely understood molecular functions. In pursuit of potential links of m 5 C with mRNA translation, we performed polysome profiling of human HeLa cell lysates and subjected RNA from resultant fractions to efficient bisulfite conversion followed by RNA sequencing (bsRNA-seq). Bioinformatic filters for rigorous site calling were devised to reduce technical noise.Results: We obtained~1000 candidate m 5 C sites in the wider transcriptome, most of which were found in mRNA. Multiple novel sites were validated by amplicon-specific bsRNA-seq in independent samples of either human HeLa, LNCaP and PrEC cells. Furthermore, RNAi-mediated depletion of either the NSUN2 or TRDMT1 m 5 C:RNA methyltransferases showed a clear dependence on NSUN2 for the majority of tested sites in both mRNAs and noncoding RNAs. Candidate m 5 C sites in mRNAs are enriched in 5′UTRs and near start codons and are embedded in a local context reminiscent of the NSUN2-dependent m 5 C sites found in the variable loop of tRNA. Analysing mRNA sites across the polysome profile revealed that modification levels, at bulk and for many individual sites, were inversely correlated with ribosome association. Conclusions: Our findings emphasise the major role of NSUN2 in placing the m 5 C mark transcriptome-wide. We further present evidence that substantiates a functional interdependence of cytosine methylation level with mRNA translation. Additionally, we identify several compelling candidate sites for future mechanistic analysis.

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“…They have mostly been characterised as either targeting tRNA (NSUN2, 3 and 6; TRDMT1) or rRNA (NSUN1, 4 and 5) (Sibbritt et al 2013;Bohnsack et al 2019). Despite their seemingly 'housekeeping' functions, these MTases display complex expression patterns during development and disease, especially in cancer, and mutations in several of them cause human genetic disease (Chi and Delgado-Olguin 2013;Blanco and Frye 2014;Begik et al 2019;Bohnsack et al 2019). One explanation for their complex biology might be that these MTases modify additional substrates outside of the tRNA and rRNA realm.…”

Section: Introductionmentioning

confidence: 99%

Multiple links between 5-methylcytosine content of mRNA and translation

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Zhang²,

Sibbritt

et al. 2020

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Abstract5-methylcytosine (m5C) is a prevalent base modification in tRNA and rRNA but it also occurs more broadly in the transcriptome, including in mRNA, where it serves incompletely understood molecular functions. In pursuit of potential links of m5C with mRNA translation, we performed polysome profiling of human HeLa cell lysates and subjected RNA from resultant fractions to efficient bisulfite conversion followed by RNA sequencing (bsRNA-seq). Bioinformatic filters for rigorous site calling were devised to reduce technical noise. We obtained ∼1,000 candidate m5C sites in the wider transcriptome, most of which were found in mRNA. Multiple novel sites were validated by amplicon-specific bsRNA-seq in independent samples of either human HeLa, LNCaP and PrEC cells. Furthermore, RNAi-mediated depletion of either the NSUN2 or TRDMT1 m5C:RNA methyltransferases showed a clear dependence on NSUN2 for the majority of tested sites in both mRNAs and noncoding RNAs. Candidate m5C sites in mRNAs are enriched in 5’UTRs and near start codons, and are commonly embedded in a local context reminiscent of the NSUN2-dependent m5C sites found in the variable loop of tRNA. Analysing mRNA sites across the polysome profile revealed that modification levels, at bulk and for many individual sites, were inversely correlated with ribosome association. Altogether, these findings emphasise the major role of NSUN2 in making this mark transcriptome-wide and further substantiate a functional interdependence of cytosine methylation level with mRNA translation.

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Integrative analyses of the RNA modification machinery reveal tissue- and cancer-specific signatures

Cited by 19 publications

References 90 publications

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

Multiple links between 5-methylcytosine content of mRNA and translation

Multiple links between 5-methylcytosine content of mRNA and translation

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