Sex differences in the methylome and transcriptome of the human liver and circulating HDL-cholesterol levels
Materias Investigacion::Ciencias de la Salud
Sex differences
Cholesterol levels
Issue Date: 
Oxford University Press
This article has been published under the terms of the Creative Commons Attribution License (CC BY;
Garcia-Calzon, S. (Sonia); Perfilyev, A. (Alexander); Mello, V.D. (Vanessa D.) de; et al. "Sex differences in the methylome and transcriptome of the human liver and circulating HDL-cholesterol levels". The Journal of Clinical Endocrinology & Metabolism. 103 (12), 2018, 4395 - 4408
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.

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