mRNA methylation in cell senescence

Casella, Gabriel; Tsitsipatis, Dimitrios; Abdelmohsen, Kotb; Gorospe, Myriam

doi:10.1002/wrna.1547

Cited by 40 publications

(31 citation statements)

References 109 publications

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“…A negative transcriptome-wide correlation between m 5 C site presence in human mRNAs and mRNA translation efficiency, as measured by ribosome profiling, was shown before [48] as was a positive transcriptome-wide association with mammalian and zebrafish mRNA stability [47,51]. Further, effects of m 5 C sites on stability and translation of several individual mRNAs in the context of cell senescence have been reported [68,69]. Given that these are opposing trends in terms of gene expression output, a reasonable guess would be that different subsets of sites drive each association.…”

Section: Discussionmentioning

confidence: 93%

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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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Section: Discussionmentioning

confidence: 93%

“…Further, a negative correlation was noted between translation of mammalian mRNAs and the presence of m 5 C sites transcriptome-wide [48]. Finally, there is a body of work on individual mRNAs and their regulation by m 5 C at the levels of stability and translation in the context of cell proliferation and senescence [68,69].…”

Section: Introductionmentioning

confidence: 97%

Multiple links between 5-methylcytosine content of mRNA and translation

et al. 2020

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“…A negative transcriptome-wide correlation between m 5 C site presence in human mRNAs and mRNA translation efficiency, as measured by ribosome profiling, was shown before (Huang et al 2019) as was a positive transcriptome-wide association with mammalian and zebrafish mRNA stability Yang et al 2019b). Further, effects of m 5 C site on stability and translation of several individual mRNAs in the context of cell senescence have been reported (Wang 2016;Casella et al 2019). Given that these are opposing trends in terms of gene expression output, a reasonable guess would be that different subsets of sites drive each association.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, there is a body of work on individual mRNAs and their regulation by m 5 C at the levels of stability and translation in the context of cell proliferation and senescence (Wang 2016;Casella et al 2019).…”

Section: Introductionmentioning

confidence: 99%

Multiple links between 5-methylcytosine content of mRNA and translation

Schümann

Zhang²,

Sibbritt

et al. 2020

Preprint

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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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“…The object of this review is to explore epigenetic modifications particularly relevant to RNA biology with a particular focus on those crucial in cardiovascular physiology and pathophysiology. For a general description of the regulation and the effects of epigenetic changes occurring at RNA level, the reader is redirected to recent articles that are more detailed in mechanistic terms [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Signalling and RNA Regulation in Cardiovascular Diseases

Mongelli¹,

Atlante²,

Bacchetti³

et al. 2019

Preprint

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RNA epigenetics is perhaps the most recent aspect of interest for translational epigeneticists. RNA modifications create such an extensive network of epigenetically driven combination whose role in physiology and pathophysiology is still far from being elucidated. Not surprisingly, some of the players determining changes into RNA structure are in common with those involved in DNA and chromatin structure regulation, while other molecules seem very specific to RNA. It is envisaged, then, that new small molecules, acting selectively on RNA epigenetic changes, will be reported soon, opening new therapeutic interventions based on the correction of the RNA epigenetic landscape. In this review, we shall summarize some aspects of RNA epigenetics limited to those in which the potential clinical translatability to cardiovascular disease is emerging.

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mRNA methylation in cell senescence

Cited by 40 publications

References 109 publications

Multiple links between 5-methylcytosine content of mRNA and translation

Multiple links between 5-methylcytosine content of mRNA and translation

Multiple links between 5-methylcytosine content of mRNA and translation

Epigenetic Signalling and RNA Regulation in Cardiovascular Diseases

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