Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels
(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.
(Less)
- author
- García-Calzón, Sonia LU ; Perfilyev, Alexander LU ; de Mello, Vanessa D. ; Pihlajamäki, Jussi and Ling, Charlotte LU
- organization
- publishing date
- 2018
- 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
-
- pmid:29846646
- scopus:85056028824
- 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
- 2024-08-21 04:50:03
@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 < 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}}, }