William Harvey Research Institute, Barts & The London School of Medicine and Dentistry, Charterhouse Square, Queen Mary University of London, London, UK.
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
Nat Commun. 2021 May 11;12(1):2655. doi: 10.1038/s41467-021-22639-6.
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.
表观基因组随着年龄的增长而恶化，可能会影响与衰老相关的疾病。tRNA 虽然只来源于 ˜46kb（<0.002%的基因组），但却是第二丰富的细胞转录本。tRNA 还通过核心翻译和其他调节作用控制已知影响衰老的代谢过程。在这里，我们研究了人类 tRNA 基因组位点的 DNA 甲基化状态。我们发现 tRNA 位点存在与年龄相关的 DNA 超甲基化的基因组富集。在 4350 个外周血 MeDIP-seq 甲基化组（16-82 岁）中的分析，分别在研究和全基因组显著水平上确定了 44 个和 21 个超甲基化的特异性 tRNA，而没有低甲基化的。验证和复制（450k 阵列和独立的靶向 Bisulfite 测序）支持了该功能单元的超甲基化。组织特异性是一个重要的驱动因素，尽管最强的一致信号也独立于主要细胞类型的变化，出现在 tRNA-iMet-CAT-1-4 和 tRNA-Ser-AGA-2-6 中。本研究全面评估了人类 tRNA 基因的基因组 DNA 甲基化状态，揭示了随着年龄的增长而出现的离散超甲基化。
