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BACKGROUND

Knowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by ageing in humans.

METHODS

We conducted a large-scale epigenome-wide association study meta-analysis of age in human skeletal muscle from 10 studies (total n = 908 muscle methylomes from men and women aged 18-89 years old). We explored the genomic context of age-related DNA methylation changes in chromatin states, CpG islands, and transcription factor binding sites and performed gene set enrichment analysis. We then integrated the DNA methylation data with known transcriptomic and proteomic age-related changes in skeletal muscle. Finally, we updated our recently developed muscle epigenetic clock (https://bioconductor.org/packages/release/bioc/html/MEAT.html).

RESULTS

We identified 6710 differentially methylated regions at a stringent false discovery rate <0.005, spanning 6367 unique genes, many of which related to skeletal muscle structure and development. We found a strong increase in DNA methylation at Polycomb target genes and bivalent chromatin domains and a concomitant decrease in DNA methylation at enhancers. Most differentially methylated genes were not altered at the mRNA or protein level, but they were nonetheless strongly enriched for genes showing age-related differential mRNA and protein expression. After adding a substantial number of samples from five datasets (+371), the updated version of the muscle clock (MEAT 2.0, total n = 1053 samples) performed similarly to the original version of the muscle clock (median of 4.4 vs. 4.6 years in age prediction error), suggesting that the original version of the muscle clock was very accurate.

CONCLUSIONS

We provide here the most comprehensive picture of DNA methylation ageing in human skeletal muscle and reveal widespread alterations of genes involved in skeletal muscle structure, development, and differentiation. We have made our results available as an open-access, user-friendly, web-based tool called MetaMeth (https://sarah-voisin.shinyapps.io/MetaMeth/).

背景

人们对骨骼肌中与年龄相关的 DNA 甲基化变化知之甚少，但在人类中，这种组织会随着年龄的增长而受到严重影响。

方法

我们对来自 10 项研究的 10 个人类骨骼肌甲基组学数据集（共 908 个男性和女性 18-89 岁骨骼肌甲基组）进行了大规模的全基因组关联研究荟萃分析。我们探索了染色质状态、CpG 岛和转录因子结合位点中与年龄相关的 DNA 甲基化变化的基因组背景，并进行了基因集富集分析。然后，我们将 DNA 甲基化数据与骨骼肌中已知的转录组和蛋白质组与年龄相关的变化进行了整合。最后，我们更新了我们最近开发的肌肉表观遗传时钟（https://bioconductor.org/packages/release/bioc/html/MEAT.html）。

结果

我们在严格的错误发现率 <0.005 下鉴定出 6710 个差异甲基化区域，涵盖了 6367 个独特的基因，其中许多与骨骼肌结构和发育有关。我们发现多梳靶基因和双价染色质区域的 DNA 甲基化显著增加，而增强子的 DNA 甲基化则相应减少。大多数差异甲基化基因在 mRNA 或蛋白质水平上没有改变，但它们在基因表达水平上与年龄相关的差异表达强烈富集。在添加了来自五个数据集的大量样本（+371）后，更新后的肌肉时钟（MEAT 2.0，共 1053 个样本）的性能与原始版本的肌肉时钟相似（年龄预测误差中位数为 4.4 岁与 4.6 岁），这表明原始版本的肌肉时钟非常准确。