Skeletal muscle methylome and transcriptome integration reveals profound sex differences related to muscle function and substrate metabolism

Clinical Epigenetics

Larisa M. Haupt¹  Lyn R. Griffiths¹  Kevin J. Ashton²  Nicholas R. Harvey³  Nir Eynon⁴  Sarah Voisin⁴  Macsue Jacques⁴  Javier Alvarez-Romero⁴  Shanie Landen⁴  Danielle Hiam⁵  Séverine Lamon⁶ 

[1] Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, Queensland University of Technology (QUT), 60 Musk Ave., 4059, Kelvin Grove, QLD, Australia;Faculty of Health Sciences and Medicine, Bond University, 4226, Gold Coast, QLD, Australia;Faculty of Health Sciences and Medicine, Bond University, 4226, Gold Coast, QLD, Australia;Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, Queensland University of Technology (QUT), 60 Musk Ave., 4059, Kelvin Grove, QLD, Australia;Institute for Health and Sport (iHeS), Victoria University, PO Box 14428, 8001, Melbourne, VIC, Australia;Institute for Health and Sport (iHeS), Victoria University, PO Box 14428, 8001, Melbourne, VIC, Australia;Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia;Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia;

关键词: DNA methylation;    Sex differences;    Skeletal muscle;    Gene expression;    Epigenome-wide study (EWAS);   

DOI  :  10.1186/s13148-021-01188-1

来源: Springer

【 摘 要 】

Nearly all human complex traits and diseases exhibit some degree of sex differences, with epigenetics being one of the main contributing factors. Various tissues display sex differences in DNA methylation; however, this has not yet been explored in skeletal muscle, despite skeletal muscle being among the tissues with the most transcriptomic sex differences. For the first time, we investigated the effect of sex on autosomal DNA methylation in human skeletal muscle across three independent cohorts (Gene SMART, FUSION, and GSE38291) using a meta-analysis approach, totalling 369 human muscle samples (222 males and 147 females), and integrated this with known sex-biased transcriptomics. We found 10,240 differentially methylated regions (DMRs) at FDR < 0.005, 94% of which were hypomethylated in males, and gene set enrichment analysis revealed that differentially methylated genes were involved in muscle contraction and substrate metabolism. We then investigated biological factors underlying DNA methylation sex differences and found that circulating hormones were not associated with differential methylation at sex-biased DNA methylation loci; however, these sex-specific loci were enriched for binding sites of hormone-related transcription factors (with top TFs including androgen (AR), estrogen (ESR1), and glucocorticoid (NR3C1) receptors). Fibre type proportions were associated with differential methylation across the genome, as well as across 16% of sex-biased DNA methylation loci (FDR < 0.005). Integration of DNA methylomic results with transcriptomic data from the GTEx database and the FUSION cohort revealed 326 autosomal genes that display sex differences at both the epigenome and transcriptome levels. Importantly, transcriptional sex-biased genes were overrepresented among epigenetic sex-biased genes (p value = 4.6e−13), suggesting differential DNA methylation and gene expression between male and female muscle are functionally linked. Finally, we validated expression of three genes with large effect sizes (FOXO3A, ALDH1A1, and GGT7) in the Gene SMART cohort with qPCR. GGT7, involved in antioxidant metabolism, displays male-biased expression as well as lower methylation in males across the three cohorts. In conclusion, we uncovered 8420 genes that exhibit DNA methylation differences between males and females in human skeletal muscle that may modulate mechanisms controlling muscle metabolism and health.

【 授权许可】

CC BY