The Genomic Loci of Specific Human TRNA Genes Exhibit Ageing-related DNA Hypermethylation

Overview

Journal Nat Commun

Specialty Biology

Date 2021 May 12

PMID 33976121

Citations 12

Authors

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

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Loss of function in causes DNA methylation signature similar to that in Wolf-Hirschhorn syndrome.

Kawai T, Kinoshita S, Takayama Y, Ohnishi E, Kamura H, Kojima K Genet Med Open. 2024; 2:101838.

PMID: 39669601 PMC: 11613750. DOI: 10.1016/j.gimo.2024.101838.

Disruption of tRNA biogenesis enhances proteostatic resilience, improves later-life health, and promotes longevity.

Malik Y, Kulaberoglu Y, Anver S, Javidnia S, Borland G, Rivera R PLoS Biol. 2024; 22(10):e3002853.

PMID: 39436952 PMC: 11495624. DOI: 10.1371/journal.pbio.3002853.

Perturbation of METTL1-mediated tRNA N- methylguanosine modification induces senescence and aging.

Fu Y, Jiang F, Zhang X, Pan Y, Xu R, Liang X Nat Commun. 2024; 15(1):5713.

PMID: 38977661 PMC: 11231295. DOI: 10.1038/s41467-024-49796-8.

Mechanisms and Delivery of tRNA Therapeutics.

Ward C, Beharry A, Tennakoon R, Rozik P, Wilhelm S, Heinemann I Chem Rev. 2024; 124(12):7976-8008.

PMID: 38801719 PMC: 11212642. DOI: 10.1021/acs.chemrev.4c00142.

Epigenomic insights into common human disease pathology.

Bell C Cell Mol Life Sci. 2024; 81(1):178.

PMID: 38602535 PMC: 11008083. DOI: 10.1007/s00018-024-05206-2.

References

Keam S, Young P, McCorkindale A, Dang T, Clancy J, Humphreys D . The human Piwi protein Hiwi2 associates with tRNA-derived piRNAs in somatic cells. Nucleic Acids Res. 2014; 42(14):8984-95. PMC: 4132735. DOI: 10.1093/nar/gku620. View

Varshney D, Vavrova-Anderson J, Oler A, Cowling V, Cairns B, White R . SINE transcription by RNA polymerase III is suppressed by histone methylation but not by DNA methylation. Nat Commun. 2015; 6:6569. PMC: 4382998. DOI: 10.1038/ncomms7569. View

Slieker R, Relton C, Gaunt T, Slagboom P, Heijmans B . Age-related DNA methylation changes are tissue-specific with ELOVL2 promoter methylation as exception. Epigenetics Chromatin. 2018; 11(1):25. PMC: 5975493. DOI: 10.1186/s13072-018-0191-3. View

Cruickshanks H, McBryan T, Nelson D, VanderKraats N, Shah P, van Tuyn J . Senescent cells harbour features of the cancer epigenome. Nat Cell Biol. 2013; 15(12):1495-506. PMC: 4106249. DOI: 10.1038/ncb2879. View

Murawski M, Szczesniak B, Zoladek T, Hopper A, Martin N, Boguta M . maf1 mutation alters the subcellular localization of the Mod5 protein in yeast. Acta Biochim Pol. 1994; 41(4):441-8. View

Teschendorff A, Menon U, Gentry-Maharaj A, Ramus S, Weisenberger D, Shen H . Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res. 2010; 20(4):440-6. PMC: 2847747. DOI: 10.1101/gr.103606.109. View

Sun L, Yu R, Dang W . Chromatin Architectural Changes during Cellular Senescence and Aging. Genes (Basel). 2018; 9(4). PMC: 5924553. DOI: 10.3390/genes9040211. View

Gomez-Roman N, Grandori C, Eisenman R, White R . Direct activation of RNA polymerase III transcription by c-Myc. Nature. 2003; 421(6920):290-4. DOI: 10.1038/nature01327. View

Dhahbi J, Spindler S, Atamna H, Yamakawa A, Boffelli D, Mote P . 5' tRNA halves are present as abundant complexes in serum, concentrated in blood cells, and modulated by aging and calorie restriction. BMC Genomics. 2013; 14:298. PMC: 3654920. DOI: 10.1186/1471-2164-14-298. View

10.

Harvey N, Javaid K, Bishop N, Kennedy S, Papageorghiou A, Fraser R . MAVIDOS Maternal Vitamin D Osteoporosis Study: study protocol for a randomized controlled trial. The MAVIDOS Study Group. Trials. 2012; 13:13. PMC: 3395865. DOI: 10.1186/1745-6215-13-13. View

11.

Ziller M, Gu H, Muller F, Donaghey J, Tsai L, Kohlbacher O . Charting a dynamic DNA methylation landscape of the human genome. Nature. 2013; 500(7463):477-81. PMC: 3821869. DOI: 10.1038/nature12433. View

12.

Horvath S, Raj K . DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet. 2018; 19(6):371-384. DOI: 10.1038/s41576-018-0004-3. View

13.

Nazor K, Altun G, Lynch C, Tran H, Harness J, Slavin I . Recurrent variations in DNA methylation in human pluripotent stem cells and their differentiated derivatives. Cell Stem Cell. 2012; 10(5):620-34. PMC: 3348513. DOI: 10.1016/j.stem.2012.02.013. View

14.

Houseman E, Accomando W, Koestler D, Christensen B, Marsit C, Nelson H . DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics. 2012; 13:86. PMC: 3532182. DOI: 10.1186/1471-2105-13-86. View

15.

Grossman R, Heath A, Ferretti V, Varmus H, Lowy D, Kibbe W . Toward a Shared Vision for Cancer Genomic Data. N Engl J Med. 2016; 375(12):1109-12. PMC: 6309165. DOI: 10.1056/NEJMp1607591. View

16.

Li S, Xu Z, Sheng J . tRNA-Derived Small RNA: A Novel Regulatory Small Non-Coding RNA. Genes (Basel). 2018; 9(5). PMC: 5977186. DOI: 10.3390/genes9050246. View

17.

Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G . The hallmarks of aging. Cell. 2013; 153(6):1194-217. PMC: 3836174. DOI: 10.1016/j.cell.2013.05.039. View

18.

Li L, Dahiya R . MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002; 18(11):1427-31. DOI: 10.1093/bioinformatics/18.11.1427. View

19.

Noma K, Cam H, Maraia R, Grewal S . A role for TFIIIC transcription factor complex in genome organization. Cell. 2006; 125(5):859-72. DOI: 10.1016/j.cell.2006.04.028. View

20.

Sagi D, Rak R, Gingold H, Adir I, Maayan G, Dahan O . Tissue- and Time-Specific Expression of Otherwise Identical tRNA Genes. PLoS Genet. 2016; 12(8):e1006264. PMC: 4999229. DOI: 10.1371/journal.pgen.1006264. View