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

García-Calzón, Sonia LU ; Perfilyev, Alexander LU orcid ; de Mello, Vanessa D. ; Pihlajamäki, Jussi and Ling, Charlotte LU orcid (2018) In The Journal of clinical endocrinology and metabolism 103(12). p.4395-4408
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... (More)

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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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
The Journal of clinical endocrinology and metabolism
volume
103
issue
12
pages
14 pages
publisher
Oxford University Press
external identifiers
  • scopus:85056028824
  • pmid:29846646
ISSN
1945-7197
DOI
10.1210/jc.2018-00423
language
English
LU publication?
yes
id
6603c42d-3ce2-46ea-9325-2a95dae94752
date added to LUP
2018-11-21 12:33:07
date last changed
2024-03-02 12:31:44
@article{6603c42d-3ce2-46ea-9325-2a95dae94752,
  abstract     = {{<p>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 &lt; 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.</p>}},
  author       = {{García-Calzón, Sonia and Perfilyev, Alexander and de Mello, Vanessa D. and Pihlajamäki, Jussi and Ling, Charlotte}},
  issn         = {{1945-7197}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{4395--4408}},
  publisher    = {{Oxford University Press}},
  series       = {{The Journal of clinical endocrinology and metabolism}},
  title        = {{Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels}},
  url          = {{http://dx.doi.org/10.1210/jc.2018-00423}},
  doi          = {{10.1210/jc.2018-00423}},
  volume       = {{103}},
  year         = {{2018}},
}