scholarly journals Comparative Transcriptome and Methylome Analysis in Human Skeletal Muscle Anabolism, Hypertrophy and Epigenetic Memory

2018 ◽  
Author(s):  
Daniel C. Turner ◽  
Robert A. Seaborne ◽  
Adam P. Sharples
Keyword(s):  
Skeletal Muscle ◽  
Dna Methylation ◽  
Large Scale ◽  
Human Skeletal Muscle ◽  
Large Data ◽  
Bioinformatic Analysis ◽  
Cancer Genes ◽  
Epigenetic Memory ◽  
Differentially Methylated Genes ◽  
Methylome Analysis

AbstractTranscriptome wide changes in human skeletal muscle after acute (anabolic) and chronic resistance exercise (RE) induced hypertrophy have been extensively determined in the literature. We have also recently undertaken DNA methylome analysis (850,000 + CpG sites) in human skeletal muscle after acute and chronic RE, detaining and retraining, where we identified an association between DNA methylation in an epigenetic memory of exercise induced skeletal muscle hypertrophy. However, it is currently unknown as to whether all the genes identified in the transcriptome studies to date are also epigenetically regulated at the DNA level after acute, chronic or repeated RE exposure. We therefore aimed to undertake large scale bioinformatical analysis by pooling the publicly available transcriptome data after acute (110 samples) and chronic RE (181 samples) and comparing these large data sets with our genome-wide DNA methylation analysis in human skeletal muscle after acute and chronic RE, detraining and retraining. Indeed, after acute RE we identified 866 up- and 936 down-regulated genes at the expression level, with 270 (out of the 866 up- regulated) identified as being hypomethylated, and 216 (out of 936 downregulated) as hypermethylated. After chronic RE we identified 2,018 up- and 430 down-regulated genes with 592 (out of 2,018 upregulated) identified as being hypomethylated and 98 (out of 430 genes downregulated) as hypermethylated. After KEGG pathway analysis, genes associated with ‘cancer’ pathways were significantly enriched in both bioinformatic analysis of the pooled transcriptome and methylome data after both acute and chronic RE. This resulted in 23 (out of 69) and 28 (out of 49) upregulated and hypomethylated and 12 (out of 37) and 2 (out of 4) downregulated and hypermethylated ‘cancer’ genes following acute and chronic RE respectively. Within skeletal muscle tissue, these ‘cancer’ genes predominant functions were associated with matrix/ actin structure and remodelling, mechano-transduction (including PTK2/Focal Adhesion Kinase and Phospholipase D-following chronic RE only), TGF-beta signalling and protein synthesis (GSK3B after acute RE only). Interestingly, 51 genes were also identified to be up/downregulated in both the acute and chronic RE pooled transcriptome analysis as well as significantly hypo/hypermethylated after acute RE, chronic RE, detraining and retraining. Five genes; FLNB, MYH9, SRGAP1, SRGN, ZMIZ1 demonstrated increased gene expression in the acute and chronic RE transcriptome and also demonstrated hypomethylation in these conditions. Importantly, these 5 genes demonstrated retained hypomethylation even during detraining (following training induced hypertrophy) when exercise was ceased and lean mass returned to baseline (pre-training) levels, identifying them as potential epigenetic memory genes. Importantly, for the first time across the transcriptome and epigenome combined, this study identifies novel differentially methylated genes associated with human skeletal muscle anabolism, hypertrophy and epigenetic memory.

scholarly journals Meta-analysis of genome-wide DNA methylation and integrative OMICs in human skeletal muscle

2020 ◽  
Author(s):  
S Voisin ◽  
M Jacques ◽  
S Landen ◽  
NR Harvey ◽  
LM Haupt ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Dna Methylation ◽  
Large Scale ◽  
Human Skeletal Muscle ◽  
Meta Analysis ◽  
Total N ◽  
Age Related ◽  
Differentially Methylated Genes ◽  
Comprehensive Picture ◽  
User Friendly

AbstractKnowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by aging in humans. Using a large-scale epigenome-wide association study (EWAS) meta-analysis of age in human skeletal muscle from 10 studies (total n = 908 human muscle methylomes), we identified 9,986 differentially methylated regions at a stringent false discovery rate < 0.005, spanning 8,748 unique genes, many of which related to skeletal muscle structure and development. We then integrated the DNA methylation results with known transcriptomic and proteomic age-related changes in skeletal muscle, and found that even though most differentially methylated genes are not altered at the mRNA or protein level, they are nonetheless strongly enriched for genes showing age-related differential expression. We provide here the most comprehensive picture of DNA methylation aging in human skeletal muscle, and have made our results available as an open-access, user-friendly, web-based tool called MetaMeth (https://sarah-voisin.shinyapps.io/MetaMeth/).

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

2021 ◽  
Author(s):  
Shanie Landen ◽  
Macsue Jacques ◽  
Danielle Hiam ◽  
Javier Alvarez Romero ◽  
Nicholas R Harvey ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Dna Methylation ◽  
Sex Differences ◽  
Complex Traits ◽  
Human Skeletal Muscle ◽  
Gene Set Enrichment Analysis ◽  
P Value ◽  
Transcriptional Level ◽  
Differentially Methylated Genes ◽  
Males And Females

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. 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.

scholarly journals Differential epigenetic and transcriptional response of the skeletal muscle carnitine palmitoyltransferase 1B (CPT1B) gene to lipid exposure with obesity

2015 ◽  
Vol 309 (4) ◽  
pp. E345-E356 ◽  
Author(s):  
Jill M. Maples ◽  
Jeffrey J. Brault ◽  
Carol A. Witczak ◽  
Sanghee Park ◽  
Monica J. Hubal ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Dna Methylation ◽  
Transcription Factor ◽  
Fatty Acid ◽  
Histone Acetylation ◽  
Human Skeletal Muscle ◽  
Epigenetic Modifications ◽  
Carnitine Palmitoyltransferase ◽  
Severely Obese ◽  
Metabolic Inflexibility

The ability to increase fatty acid oxidation (FAO) in response to dietary lipid is impaired in the skeletal muscle of obese individuals, which is associated with a failure to coordinately upregulate genes involved with FAO. While the molecular mechanisms contributing to this metabolic inflexibility are not evident, a possible candidate is carnitine palmitoyltransferase-1B (CPT1B), which is a rate-limiting step in FAO. The present study was undertaken to determine if the differential response of skeletal muscle CPT1B gene transcription to lipid between lean and severely obese subjects is linked to epigenetic modifications (DNA methylation and histone acetylation) that impact transcriptional activation. In primary human skeletal muscle cultures the expression of CPT1B was blunted in severely obese women compared with their lean counterparts in response to lipid, which was accompanied by changes in CpG methylation, H3/H4 histone acetylation, and peroxisome proliferator-activated receptor-δ and hepatocyte nuclear factor 4α transcription factor occupancy at the CPT1B promoter. Methylation of specific CpG sites in the CPT1B promoter that correlated with CPT1B transcript level blocked the binding of the transcription factor upstream stimulatory factor, suggesting a potential causal mechanism. These findings indicate that epigenetic modifications may play important roles in the regulation of CPT1B in response to a physiologically relevant lipid mixture in human skeletal muscle, a major site of fatty acid catabolism, and that differential DNA methylation may underlie the depressed expression of CPT1B in response to lipid, contributing to the metabolic inflexibility associated with severe obesity.

scholarly journals Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle

Diabetologia ◽  
2008 ◽  
Vol 51 (7) ◽  
pp. 1159-1168 ◽  
Author(s):  
T. Rönn ◽  
P. Poulsen ◽  
O. Hansson ◽  
J. Holmkvist ◽  
P. Almgren ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Dna Methylation ◽  
Human Skeletal Muscle
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