Meta‐analysis of genome‐wide DNA methylation and integrative omics of age in human skeletal muscle

Journal of Cachexia, Sarcopenia and Muscle

Lyn R. Griffiths¹  Larisa M. Haupt¹  Steve Horvath²  Nicholas R. Harvey³  Vernon G. Coffey³  Jamie‐Lee M. Thompson³  Kevin J. Ashton³  Annette Schürmann⁴  Sofiya Gancheva⁴  Michael Roden⁴  Markus Jähnert⁴  Meriem Ouni⁴  Jeffrey M. Craig⁵  Macsue Jacques⁶  Sarah Voisin⁶  Shanie Landen⁶  Nir Eynon⁶  Adam P. Sharples⁷  Sara Blocquiaux⁸  Martine Thomis⁸  Thomas M. Doering⁹  Hélène Verkindt^1,10  Robert Caiazzo^1,10  Philippe Froguel^1,10  Violetta Raverdy^1,10  François Pattou^1,10  Claudine Junien^1,11  Anne Gabory^1,11 

[1] Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, Institute of Health and Biomedical Innovation Queensland University of Technology (QUT) Kelvin Grove Qld Australia;Department of Human Genetics and Biostatistics, David Geffen School of Medicine University of California Los Angeles Los Angeles CA USA;Faculty of Health Sciences & Medicine Bond University Gold Coast Qld Australia;German Center for Diabetes Research (DZD) München‐Neuherberg Germany;IMPACT Institute Deakin University, Geelong Waurn Ponds Campus Geelong Vic. Australia;Institute for Health and Sport (iHeS) Victoria University, Footscray Melbourne Vic. Australia;Institute for Physical Performance Norwegian School of Sport Sciences Oslo Norway;Physical Activity, Sport & Health Research Group, Department of Movement Sciences KU Leuven Leuven Belgium;School of Health, Medical and Applied Sciences Central Queensland University Rockhampton Qld Australia;Univ Lille, Inserm, CHU Lille, Pasteur Institute Lille, U1190 Translational Research for Diabetes, European Genomic Institute of Diabetes Lille France;Université Paris‐Saclay, UVSQ, INRAE, BREED Jouy‐en‐Josas France;

关键词: Skeletal muscle;    Ageing;    Epigenetics;    DNA methylation;    Epigenetic clock;    Meta‐analysis;   

DOI  :  10.1002/jcsm.12741

来源: DOAJ

【 摘 要 】

Abstract 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/).

【 授权许可】

Unknown