| 1. |
- Broholm, Christa, et al.
(författare)
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Epigenome- and Transcriptome-wide Changes in Muscle Stem Cells from Low Birth Weight Men
- 2020
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Ingår i: Endocrine Research. - : Informa UK Limited. - 0743-5800 .- 1532-4206. ; 45:1, s. 58-71
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Tidskriftsartikel (refereegranskat)abstract
- Background: Being born with low birth weight (LBW) is a risk factor for muscle insulin resistance and type 2 diabetes (T2D), which may be mediated by epigenetic mechanisms programmed by the intrauterine environment. Epigenetic mechanisms exert their prime effects in developing cells. We hypothesized that muscle insulin resistance in LBW subjects may be due to early differential epigenomic and transcriptomic alterations in their immature muscle progenitor cells. Results: Muscle progenitor cells were obtained from 23 healthy young adult men born at term with LBW, and 15 BMI-matched normal birth weight (NBW) controls. The cells were subsequently cultured and differentiated into myotubes. DNA and RNA were harvested before and after differentiation for genome-wide DNA methylation and RNA expression measurements. After correcting for multiple comparisons (q ≤ 0.05), 56 CpG sites were found to be significantly, differentially methylated in myoblasts from LBW compared with NBW men, of which the top five gene-annotated CpG sites (SKI, ARMCX3, NR5A2, NEUROG, ESRRG) previously have been associated to regulation of cholesterol, fatty acid and glucose metabolism and muscle development or hypertrophy. LBW men displayed markedly decreased myotube gene expression levels of the AMPK-repressing tyrosine kinase gene FYN and the histone deacetylase gene HDAC7. Silencing of FYN and HDAC7 was associated with impaired myotube formation, which for HDAC7 reduced muscle glucose uptake. Conclusions: The data provides evidence of impaired muscle development predisposing LBW individuals to T2D is linked to and potentially caused by distinct DNA methylation and transcriptional changes including down regulation of HDAC7 and FYN in their immature myoblast stem cells.
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| 2. |
- Gillberg, Linn, et al.
(författare)
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Fasting unmasks differential fat and muscle transcriptional regulation of metabolic gene sets in low versus normal birth weight men
- 2019
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 47, s. 341-351
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Tidskriftsartikel (refereegranskat)abstract
- Background: Individuals born with low birth weight (LBW) have an increased risk of metabolic diseases when exposed to diets rich in calories and fat but may respond to fasting in a metabolically preferential manner. We hypothesized that impaired foetal growth is associated with differential regulation of gene expression and epigenetics in metabolic tissues in response to fasting in young adulthood. Methods: Genome-wide expression and DNA methylation were analysed in subcutaneous adipose tissue (SAT) and skeletal muscle from LBW and normal birth weight (NBW) men after 36 h fasting and after an isocaloric control study using microarrays. Findings: Transcriptome analyses revealed that expression of genes involved in oxidative phosphorylation (OXPHOS) and other key metabolic pathways were lower in SAT from LBW vs NBW men after the control study, but paradoxically higher in LBW vs NBW men after 36 h fasting. Thus, fasting was associated with downregulated OXPHOS and metabolic gene sets in NBW men only. Likewise, in skeletal muscle only NBW men downregulated OXPHOS genes with fasting. Few epigenetic changes were observed in SAT and muscle between the groups. Interpretation: Our results provide insights into the molecular mechanisms in muscle and adipose tissue governing a differential metabolic response in subjects with impaired foetal growth when exposed to fasting in adulthood. The results support the concept of developmental programming of metabolic diseases including type 2 diabetes. Fund: The Swedish Research Council, the Danish Council for Strategic Research, the Novo Nordisk foundation, the Swedish Foundation for Strategic Research, The European Foundation for the Study of Diabetes, The EU 6th Framework EXGENESIS grant and Rigshospitalet.
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| 3. |
- Rönn, Tina, et al.
(författare)
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Circulating triglycerides are associated with human adipose tissue DNA methylation of genes linked to metabolic disease
- 2023
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 32:11, s. 1875-1887
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulation of circulating lipids is a central element for the metabolic syndrome. However, it is not well established whether human subcutaneous adipose tissue is affected by or affect circulating lipids through epigenetic mechanisms. Hence, our aim was to investigate the association between circulating lipids and DNA methylation levels in human adipose tissue. DNA methylation and gene expression were analysed genome-wide in subcutaneous adipose tissue from two different cohorts, including 85 men and 93 women, respectively. Associations between DNA methylation and circulating levels of triglycerides, low-density lipoprotein, high-density lipoprotein and total cholesterol were analysed. Causal mediation analyses tested if adipose tissue DNA methylation mediates the effects of triglycerides on gene expression or insulin resistance. We found 115 novel associations between triglycerides and adipose tissue DNA methylation, e.g. in the promoter of RFS1, ARID2 and HOXA5 in the male cohort (P ≤ 1.1 × 10-7), and 63 associations, e.g. within the gene body of PTPRN2 and COL6A3 in the female cohort. We further connected these findings to altered mRNA expression levels in adipose tissue (e.g. HOXA5, IL11 and FAM45B). Interestingly, there was no overlap between methylation sites associated with triglycerides in men and the sites found in women, which points towards sex-specific effects of triglycerides on the epigenome. Finally, a causal mediation analysis provided support for adipose tissue DNA methylation as a partial mediating factor between circulating triglycerides and insulin resistance. This study identified novel epigenetic alterations in adipose tissue associated with circulating lipids. Identified epigenetic changes seem to mediate effects of triglycerides on insulin resistance.
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| 4. |
- Rönn, Tina, et al.
(författare)
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Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood.
- 2015
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:13, s. 3792-3813
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Tidskriftsartikel (refereegranskat)abstract
- Increased age, BMI and HbA1c levels are risk factors for several non-communicable diseases. However, the impact of these factors on the genome-wide DNA methylation pattern in human adipose tissue remains unknown. We analyzed DNA methylation of ∼480,000 sites in human adipose tissue from 96 males and 94 females, and related methylation to age, BMI and HbA1c. We also compared epigenetic signatures in adipose tissue and blood. Age was significantly associated with both altered DNA methylation and expression of 1,050 genes (e.g. FHL2, NOX4 and PLG). Interestingly, many reported epigenetic biomarkers of ageing in blood, including ELOVL2, FHL2, KLF14 and GLRA1, also showed significant correlations between adipose tissue DNA methylation and age in our study. The most significant association between age and adipose tissue DNA methylation was found upstream of ELOVL2. We identified 2,825 genes (e.g. FTO, ITIH5, CCL18, MTCH2, IRS1 and SPP1) where both DNA methylation and expression correlated with BMI. Methylation at previously reported HIF3A sites correlated significantly with BMI in females only. HbA1c (range 28-46 mmol/mol) correlated significantly with methylation of 711 sites, annotated to e.g. RAB37, TICAM1 and HLA-DPB1. Pathway analyses demonstrated that methylation levels associated with age and BMI are overrepresented among genes involved in cancer, type 2 diabetes and cardiovascular disease. Our results highlight the impact of age, BMI and HbA1c on epigenetic variation of candidate genes for metabolic diseases and cancer in human adipose tissue. Importantly, we demonstrate that epigenetic biomarkers in blood can mirror age-related epigenetic signatures in target tissues for metabolic diseases such as adipose tissue.
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