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The genomic loci of specific human tRNA genes exhibit ageing-related DNA hypermethylation

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Richard J. Acton, Wei Yuan, Fei Gao, Yudong Xia, Emma Bourne, Eva Wozniak, Jordana Bell, Karen Lillycrop, Jun Wang, Elaine Dennison, Nicholas C. Harvey, Charles A. Mein, Tim D. Spector, Pirro G. Hysi, Cyrus Cooper, Christopher G. Bell

Original languageEnglish
Article number2655
Pages (from-to)2655
Number of pages1
JournalNature Communications
Issue number1
PublishedDec 2021

Bibliographical note

Funding Information: We gratefully acknowledge the individuals from TwinsUK, Mavidos and the Hertfordshrie cohort. TwinsUK received funding from the Wellcome Trust (Ref: 081878/Z/06/Z), European Community’s Seventh Framework Programme (FP7/2007-2013), the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. Further funding support for the EpiTwin project was obtained from the European Research Council (project number 250157) and BGI. SNP Genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. The authors would like to thank Nikki Graham for her assistance with the identification and pooling of the MAVIDOS and Hertfordshire DNA samples. The authors also acknowledge the use of the IRIDIS High Performance Computing Facility, and associated support services at the University of Southampton, in the completion of this work. The MRC-LEU is supported by the Medical Research Council (MRC). R.J.A. was in receipt of a MRC Doctoral fund (1820097). Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


The epigenome has been shown to deteriorate with age, potentially impacting on ageing-related disease. tRNA, while arising from only ˜46 kb (<0.002% genome), is the second most abundant cellular transcript. tRNAs also control metabolic processes known to affect ageing, through core translational and additional regulatory roles. Here, we interrogate the DNA methylation state of the genomic loci of human tRNA. We identify a genomic enrichment for age-related DNA hypermethylation at tRNA loci. Analysis in 4,350 MeDIP-seq peripheral-blood DNA methylomes (16-82 years), identifies 44 and 21 hypermethylating specific tRNAs at study-and genome-wide significance, respectively, contrasting with none hypomethylating. Validation and replication (450k array and independent targeted Bisuphite-sequencing) supported the hypermethylation of this functional unit. Tissue-specificity is a significant driver, although 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 presents a comprehensive evaluation of the genomic DNA methylation state of human tRNA genes and reveals a discreet hypermethylation with advancing age.

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