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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."xsd:string
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http://purl.uniprot.org/citations/29846646http://purl.uniprot.org/core/author"Ling C."xsd:string
http://purl.uniprot.org/citations/29846646http://purl.uniprot.org/core/author"Pihlajamaki J."xsd:string
http://purl.uniprot.org/citations/29846646http://purl.uniprot.org/core/author"de Mello V.D."xsd:string
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http://purl.uniprot.org/citations/29846646http://purl.uniprot.org/core/date"2018"xsd:gYear
http://purl.uniprot.org/citations/29846646http://purl.uniprot.org/core/name"J Clin Endocrinol Metab"xsd:string
http://purl.uniprot.org/citations/29846646http://purl.uniprot.org/core/pages"4395-4408"xsd:string
http://purl.uniprot.org/citations/29846646http://purl.uniprot.org/core/title"Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels."xsd:string
http://purl.uniprot.org/citations/29846646http://purl.uniprot.org/core/volume"103"xsd:string
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