Dataset Information

Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels.

ABSTRACT: Context:Epigenetics may contribute to sex-specific differences in human liver metabolism. Objective:To study the impact of sex on DNA methylation and gene expression in human liver. Design/Setting:Cross-sectional, Kuopio Obesity Surgery Study. Participants/Intervention:We analyzed DNA methylation with the Infinium HumanMethylation450 BeadChip in liver of an obese population (34 males, 61 females). Females had a higher high-density lipoprotein (HDL)-cholesterol levels compared with males. Gene expression was measured with the HumanHT-12 Expression BeadChip in a subset of 42 participants. Results:Females displayed higher average methylation in the X-chromosome, whereas males presented higher methylation in autosomes. We found 9455 CpG sites in the X-chromosome and 33,205 sites in autosomes with significant methylation differences in liver between sexes (q < 0.05). When comparing our findings with published studies, 95% of the sex-specific differences in liver methylation in the X-chromosome were also found in pancreatic islets and brain, and 26 autosomal sites showed sex-specific methylation differences in the liver as well as in other human tissues. Furthermore, this sex-specific methylation profile in liver was associated with hepatic gene expression changes between males and females. Notably, females showed higher HDL-cholesterol levels, which were associated with higher KDM6A expression and epigenetic differences in human liver. Accordingly, silencing of KDM6A in cultured liver cells reduced HDL-cholesterol levels and APOA1 expression, which is a major component of HDL particles. Conclusions:Human liver has a sex-specific methylation profile in both the X-chromosome and autosomes, which associates with hepatic gene expression changes and HDL-cholesterol. We identified KDM6A as a novel target that regulates HDL-cholesterol levels.

SUBMITTER: Garcia-Calzon S

PROVIDER: S-EPMC6212806 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other

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Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels.

García-Calzón Sonia S Perfilyev Alexander A de Mello Vanessa D VD Pihlajamäki Jussi J Ling Charlotte C

The Journal of clinical endocrinology and metabolism 20181201 12

<h4>Context</h4>Epigenetics may contribute to sex-specific differences in human liver metabolism.<h4>Objective</h4>To study the impact of sex on DNA methylation and gene expression in human liver.<h4>Design/setting</h4>Cross-sectional, Kuopio Obesity Surgery Study.<h4>Participants/intervention</h4>We analyzed DNA methylation with the Infinium HumanMethylation450 BeadChip in liver of an obese population (34 males, 61 females). Females had a higher high-density lipoprotein (HDL)-cholesterol levels ...[more]

PMID: 29846646

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Project description: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. Supplementary Information The online version contains supplementary material available at 10.1186/s13148-021-01188-1.

Dataset Information

Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels.

Publications

Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels.

Similar Datasets

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