The Genomic Loci of Specific Human tRNA Genes Exhibit Ageing-Related DNA Hypermethylation

Abstract The epigenome deteriorates with age, potentially impacting on ageing-related disease. Here, we interrogate the DNA methylation state of the genomic loci of human tRNA. Whilst arising from only ~46kb (<0.002% genome), this information transfer machinery is the second most abundant cellula...

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Published inbioRxiv
Main Authors Acton, Richard J, Yuan, Wei, Gao, Fei, Xia, Yudong, Bourne, Emma, Wozniak, Eva, Bell, Jordana, Lillycrop, Karen, Wang, Jun, Dennison, Elaine, Harvey, Nicholas, Mein, Charles A, Spector, Tim D, Hysi, Pirro G, Cooper, Cyrus, Bell, Christopher G
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 01.06.2020
Subjects
Aging
Amino acid sequence
Bisulfite
CpG islands
Deoxyribonucleic acid
DNA
DNA methylation
DNA sequencing
Gene loci
Genomes
Nucleotide sequence
Peripheral blood
tRNA Ile
tRNA iMet
tRNA Ser
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Summary:Abstract The epigenome deteriorates with age, potentially impacting on ageing-related disease. Here, we interrogate the DNA methylation state of the genomic loci of human tRNA. Whilst arising from only ~46kb (<0.002% genome), this information transfer machinery is the second most abundant cellular transcript. tRNAs also control metabolic processes known to affect ageing, through core translational and additional regulatory roles. We identified a genomic enrichment for age-related DNA hypermethylation at tRNA loci. Analysis in 4,350 MeDIP-seq peripheral-blood DNA methylomes (16-82 years), classified 44 and 21 hypermethylating specific tRNAs at study- and genome-wide significance, respectively, contrasting with 0 hypomethylating. Validation and replication (450k array & independent targeted Bisuphite-sequencing) supported thehypermethylation of this functional unit. The strongest consistent signals, also independent of major cell-type change, occur in tRNA-iMet-CAT-1-4 and tRNA-Ser-AGA-2-6. This study is this first comprehensive evaluation of the genomic DNA methylation state of human tRNA genes and reveals a discreet hypermethylation with advancing age. Competing Interest Statement The authors have declared no competing interest. Footnotes * Various changes in response to reviewers feedback, briefly: - Section on tsRNA expression dropped. - More detail on the genomic context of age-hypermethylating tRNAs. - Consolidation of figures into panels and improved legends - Additional supplementary data - Human/Mouse orthologs comparison * https://github.com/RichardJActon/tRNA_paper_code
DOI:10.1101/870352