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Alexander Perfilyev

Assistant researcher

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

Author

  • Sonia García-Calzón
  • Alexander Perfilyev
  • Vanessa D. de Mello
  • Jussi Pihlajamäki
  • Charlotte Ling

Summary, in English

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.

Department/s

  • Diabetes - Epigenetics
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2018

Language

English

Pages

4395-4408

Publication/Series

The Journal of clinical endocrinology and metabolism

Volume

103

Issue

12

Document type

Journal article

Publisher

Oxford University Press

Topic

  • Gastroenterology and Hepatology
  • Medical Genetics

Status

Published

Research group

  • Diabetes - Epigenetics

ISBN/ISSN/Other

  • ISSN: 1945-7197