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- García-Calzón, Sonia, et al.
(author)
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Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels
- 2018
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 103:12, s. 4395-4408
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Journal article (peer-reviewed)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 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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| 2. |
- Kokosar, Milana, et al.
(author)
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A Single Bout of Electroacupuncture Remodels Epigenetic and Transcriptional Changes in Adipose Tissue in Polycystic Ovary Syndrome
- 2018
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
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Journal article (peer-reviewed)abstract
- A single bout of electroacupuncture results in muscle contractions and increased whole body glucose uptake in women with polycystic ovary syndrome (PCOS). Women with PCOS have transcriptional and epigenetic alterations in the adipose tissue and we hypothesized that electroacupuncture induces epigenetic and transcriptional changes to restore metabolic alterations. Twenty-one women with PCOS received a single bout of electroacupuncture, which increased the whole body glucose uptake. In subcutaneous adipose tissue biopsies, we identified treatment-induced expression changes of 2369 genes (Q < 0.05) and DNA methylation changes of 7055 individual genes (Q = 0.11). The largest increase in expression was observed for FOSB (2405%), and the largest decrease for LOC100128899 (54%). The most enriched pathways included Acute phase response signaling and LXR/RXR activation. The DNA methylation changes ranged from 1-16%, and 407 methylation sites correlated with gene expression. Among genes known to be differentially expressed in PCOS, electroacupuncture reversed the expression of 80 genes, including PPAR gamma and ADIPOR2. Changes in the expression of Nr4 alpha 2 and Junb are reversed by adrenergic blockers in rats demonstrating that changes in gene expression, in part, is due to activation of the sympathetic nervous system. In conclusion, low-frequency electroacupuncture with muscle contractions remodels epigenetic and transcriptional changes that elicit metabolic improvement.
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| 3. |
- Perfilyev, Alexander
(author)
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DNA methylation patterns in human adipose tissue in relation to diet and type 2 diabetes
- 2018
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Doctoral thesis (other academic/artistic)abstract
- Type 2 diabetes (T2D) is a common metabolic disease and its prevalence is increasing worldwide. Adipose tissue plays an important role in metabolic processes. Environmental factors may affect metabolic phenotypes and epigenetics may mediate this influence. We used Illumina 450k microarrays to study correlations between epigenetic patterns in human adipose tissue and environmental factors such as high-fat diets, impaired intrauterine environment and low birth weight as well as with type 2 diabetes.In study 1 we investigated whether the DNA methylation pattern in human adipose tissue is affected differently by a 7-week exposure to a diet high in either polyunsaturated fatty acids or saturated fatty acids. We found differences in methylation related to general fat overfeeding as well as between the two dietary groups.In study 2 we studied the effect of 5 days of overfeeding with a high fat diet on DNA methylation in adipose tissue compared to a control diet. The participants were either born with a normal or low birth weight and it allowed also to compare the effects of the diets on these two groups separately. There were differences in methylation between subjects born with a low compared with normal birth weight.In study 3 we used adipose tissue of a cohort of 14 monozygotic twin pairs discordant for type 2 diabetes in order to eliminate most of known confounding factors in comparing DNA methylation patterns as well as a case- control cohort for T2D. We found numerous differences in methylation in adipose tissue from subjects with T2D compared with controls, while less differences were found in the discordant twins.In study 4 we compared DNA methylation in adipose-derived stem and differentiated cells in subjects born with a low or normal birth weight. We found differences in gene expression in adipose-derived stem cells between low birth weight and normal birth weight groups but did not identify differences in methylation patterns possibly due to lack of statistical power.Overall, these studies contribute to a better understanding of the influence of environmental factors and type 2 diabetes on DNA methylation in human adipose tissue.
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