Nuclear genetic regulation of human mitochondrial RNA modification

At, Ali; Idaghdour, Youssef; Hodgkinson, Alan

doi:10.1101/666339

Cited by 4 publications

(4 citation statements)

References 68 publications

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“…A basal level of p9 methylation is required for proper tRNA folding and stability [7] and the degree of methylation at p9 sites has been shown by other groups to have low inter-individual variability [43]. In addition, p9 hypermethylation has been observed in other age-related diseases such as cancer [44].…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

2020

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Background: Methylation of mitochondrial tRNAs (mt-tRNA) at the 9th position ("p9 site") is known to impact translational efficiency and downstream mitochondrial function; however, direct assessment of mt-RNA methylation is challenging. Recent RNA sequence-based methods have been developed to reliably identify post-transcriptional methylation. Though p9 methylation has been studied in healthy human populations and in the context of cancer, it has not yet been analyzed in neurodegenerative disease, where mitochondrial dysfunction is a prominent and early hallmark of disease progression. Methods: Mitochondrial p9 methylation was inferred from multi-allelic calls in RNA-seq data. Gene-based association studies were performed in FUMA. Correlations between nuclear gene expression and p9 methylation were tested using Spearman's rho. Fisher's Exact test was used in PANTHER and IPA to test for overrepresentation and enrichment of biological processes and pathways in the top nuclear genes correlated with p9 methylation. Results: Variable methylation was observed at 11 p9 sites in post-mortem cerebellar tissue of elderly subjects who were either healthy or diagnosed with Alzheimer's disease (AD), progressive supranuclear palsy (PSP) or pathological aging (PA). Similarities in degree of methylation were observed between AD and PSP. Certain nuclear encoded genes were identified as significantly associated with p9 methylation. Expression of 5300 nuclear encoded genes was significantly correlated with p9 methylation, with AD and PSP subjects exhibiting similar expression profiles. Overrepresentation and enrichment testing using the top transcripts revealed enrichment for a number of molecular processes, terms and pathways including many of which that were mitochondrial-related. Conclusion: With mitochondrial dysfunction being an established hallmark of neurodegenerative disease pathophysiology, this work sheds light on the potential molecular underpinnings of this dysfunction. Here we show overlap in cerebellar pathophysiology between common tauopathies such as Alzheimer's disease and progressive supranuclear palsy. Whether p9 hypermethylation is a cause or consequence of pathology remains an area of focus.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

2020

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“…A basal level of p9 methylation is required for proper tRNA folding and stability (7) and the degree of methylation at p9 sites has been shown by other groups to have low inter-individual variability (42). In addition, p9 hypermethylation has been observed in other age-related diseases such as cancer (43).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

Silzer

Pathak

Phillips

2020

Preprint

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Background. Methylation of mitochondrial tRNAs (mt-tRNA) at the 9th position (“p9 site”) is known to impact translational efficiency and downstream mitochondrial function; however, direct assessment of mt-RNA methylation is challenging. Recent RNA sequence-based methods have been developed to reliably identify post-transcriptional methylation. Though p9 methylation has been studied in healthy human populations and in the context of cancer, it has not yet been analyzed in neurodegenerative disease, where mitochondrial dysfunction is a prominent and early hallmark of disease progression. Results. Here we show variable methylation at 11 p9 sites in post-mortem cerebellar tissue of elderly subjects who were either healthy or diagnosed with Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) or pathological aging (PA). Similarities in degree of methylation were observed between AD and PSP. Expression of 5300 genes was significantly correlated with p9 methylation, with AD and PSP subjects exhibiting similar expression profiles. Overrepresentation and enrichment testing using the top transcripts revealed enrichment for a number of molecular processes, terms and pathways including many of which were mitochondrial-related. Conclusion. With mitochondrial dysfunction being an established hallmark of neurodegenerative disease pathophysiology, this work sheds light on the potential molecular underpinnings of this dysfunction. Here we show overlap in cerebellar pathophysiology between common tauopathies such as Alzheimer’s disease and progressive supranuclear palsy. Whether p9 hypermethylation is a cause or consequence of pathology remains an area of focus.

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“…A basal level of p9 methylation is required for proper tRNA folding and stability (38) and the degree of methylation at p9 sites has been shown by other groups to have low inter-individual variability (39). In addition, p9 hypermethylation has been observed in other age-related diseases such as cancer (40).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

Silzer

Pathak

Phillips

2020

Preprint

View full text Add to dashboard Cite

Background Methylation of mitochondrial tRNAs (mt-tRNA) at the 9th position (“p9 site”) is known to impact translational efficiency and downstream mitochondrial function; however, direct assessment of mt-RNA methylation is challenging. Recent RNA sequence-based methods have been developed to reliably identify post-transcriptional methylation. Though p9 methylation has been studied in healthy human populations and in the context of cancer, it has not yet been analyzed in neurodegenerative disease, where mitochondrial dysfunction is a prominent and early hallmark of disease progression.Results Here we show variable methylation at 11 p9 sites in post-mortem cerebellar tissue of elderly subjects who were either healthy or diagnosed with Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) or pathological aging (PA). Similarities in degree of methylation were observed between AD and PSP. Expression of 5300 genes was significantly correlated with p9 methylation, with AD and PSP subjects exhibiting similar expression profiles. The top 100 transcripts were found to be enriched for mitochondrial-related toxicity. Overrepresentation testing using the top 1000 transcripts revealed enrichment for a number of molecular processes and terms including some which were mitochondrial-related.Conclusion With mitochondrial dysfunction being an established hallmark of neurodegenerative disease pathophysiology, this work sheds light on the potential molecular underpinnings of this dysfunction. Here we show overlap in cerebellar pathophysiology between common tauopathies such as Alzheimer’s disease and progressive supranuclear palsy. Whether p9 hypermethylation is a cause or consequence of pathology remains an area of focus.

show abstract

Nuclear genetic regulation of human mitochondrial RNA modification

Cited by 4 publications

References 68 publications

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

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