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Genome-wide DNA methylation and transcriptome integration reveal distinct sex differences in skeletal muscle

View ORCID ProfileShanie Landen, View ORCID ProfileMacsue Jacques, View ORCID ProfileDanielle Hiam, Javier Alvarez, Nicholas R Harvey, Larisa M. Haupt, Lyn R. Griffiths, Kevin J Ashton, View ORCID ProfileSéverine Lamon, View ORCID ProfileSarah Voisin, View ORCID ProfileNir Eynon
doi: https://doi.org/10.1101/2021.03.16.435733
Shanie Landen
1Institute for Health and Sport (iHeS), Victoria University, Melbourne, Australia
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Macsue Jacques
1Institute for Health and Sport (iHeS), Victoria University, Melbourne, Australia
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Danielle Hiam
1Institute for Health and Sport (iHeS), Victoria University, Melbourne, Australia
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Javier Alvarez
1Institute for Health and Sport (iHeS), Victoria University, Melbourne, Australia
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Nicholas R Harvey
2Faculty of Health Sciences & Medicine, Bond University, Gold Coast, QLD 4226, Australia
3Queensland University of Technology (QUT), Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, 60 Musk Ave., Kelvin Grove, Queensland 4059, Australia
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Larisa M. Haupt
3Queensland University of Technology (QUT), Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, 60 Musk Ave., Kelvin Grove, Queensland 4059, Australia
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Lyn R. Griffiths
3Queensland University of Technology (QUT), Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, 60 Musk Ave., Kelvin Grove, Queensland 4059, Australia
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Kevin J Ashton
2Faculty of Health Sciences & Medicine, Bond University, Gold Coast, QLD 4226, Australia
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Séverine Lamon
4Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia
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Sarah Voisin
1Institute for Health and Sport (iHeS), Victoria University, Melbourne, Australia
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Nir Eynon
1Institute for Health and Sport (iHeS), Victoria University, Melbourne, Australia
5Murdoch Children’s Research Institute, Melbourne, Australia
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  • For correspondence: Nir.Eynon@vu.edu.au
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Abstract

Nearly all human complex traits and diseases exhibit some degree of sex differences, and epigenetics contributes to these differences as DNA methylation shows sex differences in various tissues. However, skeletal muscle epigenetic sex differences remain largely unexplored, yet skeletal muscle displays distinct sex differences at the transcriptome level. We conducted a large-scale meta-analysis of autosomal DNA methylation sex differences in human skeletal muscle in three separate cohorts (Gene SMART, FUSION, and GSE38291), totalling n = 369 human muscle samples (n = 222 males, n = 147 females). 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 metabolism. We then integrated our epigenetic results with transcriptomic data from the GTEx database and the FUSION cohort. Altogether, we identified 326 autosomal genes that display sex differences at both the DNA methylation, and transcriptome levels. Importantly, sex-biased genes at the transcriptional level were overrepresented among the sex-biased genes at the epigenetic level (p-value = 4.6e-13), which suggests differential DNA methylation and gene expression between males and females in 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 muscle metabolism, displays male-biased expression in skeletal muscle across the three cohorts, as well as lower methylation in males. In conclusion, we uncovered thousands of genes that exhibit DNA methylation differences between the males and females in human skeletal muscle that may modulate mechanisms controlling muscle metabolism and health.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* Sarah Voisin and Nir Eynon are co-senior authors

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted March 17, 2021.
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Genome-wide DNA methylation and transcriptome integration reveal distinct sex differences in skeletal muscle
Shanie Landen, Macsue Jacques, Danielle Hiam, Javier Alvarez, Nicholas R Harvey, Larisa M. Haupt, Lyn R. Griffiths, Kevin J Ashton, Séverine Lamon, Sarah Voisin, Nir Eynon
bioRxiv 2021.03.16.435733; doi: https://doi.org/10.1101/2021.03.16.435733
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Genome-wide DNA methylation and transcriptome integration reveal distinct sex differences in skeletal muscle
Shanie Landen, Macsue Jacques, Danielle Hiam, Javier Alvarez, Nicholas R Harvey, Larisa M. Haupt, Lyn R. Griffiths, Kevin J Ashton, Séverine Lamon, Sarah Voisin, Nir Eynon
bioRxiv 2021.03.16.435733; doi: https://doi.org/10.1101/2021.03.16.435733

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