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| 4. |
- Jufvas, Åsa, et al.
(författare)
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Global differences in specific histone H3 methylation are associated with overweight and type 2 diabetes.
- 2013
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Ingår i: Clinical Epigenetics. - : BioMed Central. - 1868-7083 .- 1868-7075. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Epidemiological evidence indicates yet unknown epigenetic mechanisms underlying a propensity for overweight and type 2 diabetes. We analyzed the extent of methylation at lysine 4 and lysine 9 of histone H3 in primary human adipocytes from 43 subjects using modification-specific antibodies.RESULTS: The level of lysine 9 dimethylation was stable, while adipocytes from type 2 diabetic and non-diabetic overweight subjects exhibited about 40% lower levels of lysine 4 dimethylation compared with cells from normal-weight subjects. In contrast, trimethylation at lysine 4 was 40% higher in adipocytes from overweight diabetic subjects compared with normal-weight and overweight non-diabetic subjects. There was no association between level of modification and age of subjects.CONCLUSIONS: The findings define genome-wide molecular modifications of histones in adipocytes that are directly associated with overweight and diabetes, and thus suggest a molecular basis for existing epidemiological evidence of epigenetic inheritance.
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| 6. |
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| 7. |
- Ahlén Bergman, Emma, et al.
(författare)
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Increased CD4+ T cell lineage commitment determined by CpG methylation correlates with better prognosis in urinary bladder cancer patients
- 2018
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Ingår i: Clinical Epigenetics. - : BMC. - 1868-7083 .- 1868-7075. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Urinary bladder cancer is a common malignancy worldwide. Environmental factors and chronic inflammation are correlated with the disease risk. Diagnosis is performed by transurethral resection of the bladder, and patients with muscle invasive disease preferably proceed to radical cystectomy, with or without neoadjuvant chemotherapy. The anti-tumour immune responses, known to be initiated in the tumour and draining lymph nodes, may play a major role in future treatment strategies. Thus, increasing the knowledge of tumour-associated immunological processes is important. Activated CD4+ T cells differentiate into four main separate lineages: Th1, Th2, Th17 and Treg, and they are recognized by their effector molecules IFN-γ, IL-13, IL-17A, and the transcription factor Foxp3, respectively. We have previously demonstrated signature CpG sites predictive for lineage commitment of these four major CD4+ T cell lineages. Here, we investigate the lineage commitment specifically in tumour, lymph nodes and blood and relate them to the disease stage and response to neoadjuvant chemotherapy.RESULTS: Blood, tumour and regional lymph nodes were obtained from patients at time of transurethral resection of the bladder and at radical cystectomy. Tumour-infiltrating CD4+ lymphocytes were significantly hypomethylated in all four investigated lineage loci compared to CD4+ lymphocytes in lymph nodes and blood (lymph nodes vs tumour-infiltrating lymphocytes: IFNG -4229 bp p < 0.0001, IL13 -11 bp p < 0.05, IL17A -122 bp p < 0.01 and FOXP3 -77 bp p > 0.05). Examination of individual lymph nodes displayed different methylation signatures, suggesting possible correlation with future survival. More advanced post-cystectomy tumour stages correlated significantly with increased methylation at the IFNG -4229 bp locus. Patients with complete response to neoadjuvant chemotherapy displayed significant hypomethylation in CD4+ T cells for all four investigated loci, most prominently in IFNG p < 0.0001. Neoadjuvant chemotherapy seemed to result in a relocation of Th1-committed CD4+ T cells from blood, presumably to the tumour, indicated by shifts in the methylation patterns, whereas no such shifts were seen for lineages corresponding to IL13, IL17A and FOXP3.CONCLUSION: Increased lineage commitment in CD4+ T cells, as determined by demethylation in predictive CpG sites, is associated with lower post-cystectomy tumour stage, complete response to neoadjuvant chemotherapy and overall better outcome, suggesting epigenetic profiling of CD4+ T cell lineages as a useful readout for clinical staging.
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| 8. |
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| 9. |
- Barazeghi, Elham, et al.
(författare)
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5-Hydroxymethylcytosine discriminates between parathyroid adenoma and carcinoma
- 2016
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7083 .- 1868-7075. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Primary hyperparathyroidism is characterized by enlarged parathyroid glands due to an adenoma (80-85 %) or multiglandular disease (similar to 15 %) causing hypersecretion of parathyroid hormone (PTH) and generally hypercalcemia. Parathyroid cancer is rare (<1-5 %). The epigenetic mark 5-hydroxymethylcytosine (5hmC) is reduced in various cancers, and this may involve reduced expression of the ten-eleven translocation 1 (TET1) enzyme. Here, we have performed novel experiments to determine the 5hmC level and TET1 protein expression in 43 parathyroid adenomas (PAs) and 17 parathyroid carcinomas (PCs) from patients who had local invasion or metastases and to address a potential growth regulatory role of TET1. Results: The global 5hmC level was determined by a semi-quantitative DNA immune-dot blot assay in a smaller number of tumors. The global 5hmC level was reduced in nine PCs and 15 PAs compared to four normal tissue samples (p < 0.05), and it was most severely reduced in the PCs. By immunohistochemistry, all 17 PCs stained negatively for 5hmC and TET1 showed negative or variably heterogeneous staining for the majority. All 43 PAs displayed positive 5hmC staining, and a similar aberrant staining pattern of 5hmC and TET1 was seen in about half of the PAs. Western blotting analysis of two PCs and nine PAs showed variable TET1 protein expression levels. A significantly higher tumor weight was associated to PAs displaying a more severe aberrant staining pattern of 5hmC and TET1. Overexpression of TET1 in a colony forming assay inhibited parathyroid tumor cell growth. Conclusions: 5hmC can discriminate between PAs and PCs. Whether 5hmC represents a novel marker for malignancy warrants further analysis in additional parathyroid tumor cohorts. The results support a growth regulatory role of TET1 in parathyroid tissue.
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| 10. |
- Bauden, Monika, et al.
(författare)
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Circulating nucleosomes as epigenetic biomarkers in pancreatic cancer.
- 2015
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7075 .- 1868-7083. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To improve the prognosis of patients with pancreatic cancer, new biomarkers are required for earlier, pre-symptomatic diagnosis. Epigenetic mutations take place at the earliest stages of tumorigenesis and therefore offer new approaches for detecting and diagnosing disease. Nucleosomes are the repeating subunits of DNA and histone proteins that constitute human chromatin. Because of their release into the circulation, intact nucleosome levels in serum or plasma can serve as diagnostic disease biomarkers, and elevated levels have been reported in various cancers. However, quantifying nucleosomes in the circulation for cancer detection has been challenging due to nonspecific elevation in sera of patients with benign diseases. Here, we report for the first time differential, disease-associated epigenetic profiles of intact cell-free nucleosomes (cfnucleosomes) containing specific DNA and histone modifications as well as histone variants circulating in the blood. The study comprised serum samples from 59 individuals, including 25 patients with resectable pancreatic cancer, 10 patients with benign pancreatic disease, and 24 healthy individuals using Nucleosomics(®), a novel ELISA method.
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| 11. |
- Borssén, Magnus, et al.
(författare)
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DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia
- 2018
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Ingår i: Clinical Epigenetics. - : BIOMED CENTRAL LTD. - 1868-7083 .- 1868-7075. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Few biological markers are associated with survival after relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In pediatric T-cell ALL, we have identified promoter-associated methylation alterations that correlate with prognosis. Here, the prognostic relevance of CpG island methylation phenotype (CIMP) classification was investigated in pediatric BCP-ALL patients.Methods: Six hundred and one BCP-ALL samples from Nordic pediatric patients (age 1-18) were CIMP classified at initial diagnosis and analyzed in relation to clinical data.Results: Among the 137 patients that later relapsed, patients with a CIMP-profile (n = 42) at initial diagnosis had an inferior overall survival (pOS(5years) 33%) compared to CIMP+ patients (n = 95, pOS(5years) 65%) (p = 0.001), which remained significant in a Cox proportional hazards model including previously defined risk factors.Conclusion: CIMP classification is a strong candidate for improved risk stratification of relapsed BCP-ALL.
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| 12. |
- Bovinder Ylitalo, Erik, et al.
(författare)
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A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer
- 2021
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Ingår i: Clinical Epigenetics. - : BioMed Central. - 1868-7083 .- 1868-7075. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with metastatic prostate cancer (PC) are treated with androgen deprivation therapy (ADT) that initially reduces metastasis growth, but after some time lethal castration-resistant PC (CRPC) develops. A better understanding of the tumor biology in bone metastases is needed to guide further treatment developments. Subgroups of PC bone metastases based on transcriptome profiling have been previously identified by our research team, and specifically, heterogeneities related to androgen receptor (AR) activity have been described. Epigenetic alterations during PC progression remain elusive and this study aims to explore promoter gene methylation signatures in relation to gene expression and tumor AR activity.Materials and methods: Genome-wide promoter-associated CpG methylation signatures of a total of 94 tumor samples, including paired non-malignant and malignant primary tumor areas originating from radical prostatectomy samples (n = 12), and bone metastasis samples of separate patients with hormone-naive (n = 14), short-term castrated (n = 4) or CRPC (n = 52) disease were analyzed using the Infinium Methylation EPIC arrays, along with gene expression analysis by Illumina Bead Chip arrays (n = 90). AR activity was defined from expression levels of genes associated with canonical AR activity.Results: Integrated epigenome and transcriptome analysis identified pronounced hypermethylation in malignant compared to non-malignant areas of localized prostate tumors. Metastases showed an overall hypomethylation in relation to primary PC, including CpGs in the AR promoter accompanied with induction of AR mRNA levels. We identified a Methylation Classifier for Androgen receptor activity (MCA) signature, which separated metastases into two clusters (MCA positive/negative) related to tumor characteristics and patient prognosis. The MCA positive metastases showed low methylation levels of genes associated with canonical AR signaling and patients had a more favorable prognosis after ADT. In contrast, MCA negative patients had low AR activity associated with hypermethylation of AR-associated genes, and a worse prognosis after ADT.Conclusions: A promoter methylation signature classifies PC bone metastases into two groups and predicts tumor AR activity and patient prognosis after ADT. The explanation for the methylation diversities observed during PC progression and their biological and clinical relevance need further exploration.
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| 13. |
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| 14. |
- Ciuculete, Diana-Maria, et al.
(författare)
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meQTL and ncRNA functional analyses of 102 GWAS-SNPs associated with depression implicate HACE1 and SHANK2 genes
- 2020
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Ingår i: Clinical Epigenetics. - : BMC. - 1868-7083 .- 1868-7075. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Little is known about how genetics and epigenetics interplay in depression. Evidence suggests that genetic variants may change vulnerability to depression by modulating DNA methylation (DNAm) and non-coding RNA (ncRNA) levels. Therefore, the aim of the study was to investigate the effect of the genetic variation, previously identified in the largest genome-wide association study for depression, on proximal DNAm and ncRNA levels. Results We performed DNAm quantitative trait locus (meQTL) analysis in two independent cohorts (totaln= 435 healthy individuals), testing associations between 102 single-nucleotide polymorphisms (SNPs) and DNAm levels in whole blood. We identified and replicated 64 SNP-CpG pairs (p(adj.)< 0.05) with meQTL effect. Lower DNAm at cg02098413 located in theHACE1promoter conferred by the risk allele (C allele) at rs1933802 was associated with higher risk for depression (p(raw)= 0.014, DNAm = 2.3%). In 1202 CD14+ cells sorted from blood, DNAm at cg02088412 positively correlated withHACE1mRNA expression. Investigation in postmortem brain tissue of adults diagnosed with major depressive disorder (MDD) indicated 1% higher DNAm at cg02098413 in neurons and lowerHACE1mRNA expression in CA1 hippocampus of MDD patients compared with healthy controls (p= 0.008 and 0.012, respectively). Expression QTL analysis in blood of 74 adolescent revealed that hsa-miR-3664-5p was associated with rs7117514 (SHANK2) (p(adj.)= 0.015, mRNA difference = 5.2%). Gene ontology analysis of the miRNA target genes highlighted implication in neuronal processes. Conclusions Collectively, our findings from a multi-tissue (blood and brain) and multi-layered (genetic, epigenetic, transcriptomic) approach suggest that genetic factors may influence depression by modulating DNAm and miRNA levels. Alterations atHACE1andSHANK2loci imply potential mechanisms, such as oxidative stress in the brain, underlying depression. Our results deepened the knowledge of molecular mechanisms in depression and suggest new epigenetic targets that should be further evaluated.
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| 15. |
- Danielsson, Anna, 1973, et al.
(författare)
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Accumulation of DNA methylation alterations in paediatric glioma stem cells following fractionated dose irradiation
- 2020
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7075 .- 1868-7083. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Radiation is an important therapeutic tool. However, radiotherapy has the potential to promote co-evolution of genetic and epigenetic changes that can drive tumour heterogeneity, formation of radioresistant cells and tumour relapse. There is a clinical need for a better understanding of DNA methylation alterations that may follow radiotherapy to be able to prevent the development of radiation-resistant cells. Methods We examined radiation-induced changes in DNA methylation profiles of paediatric glioma stem cells (GSCs) in vitro. Five GSC cultures were irradiated in vitro with repeated doses of 2 or 4 Gy. Radiation was given in 3 or 15 fractions. DNA methylation profiling using Illumina DNA methylation arrays was performed at 14 days post-radiation. The cellular characteristics were studied in parallel. Results Few fractions of radiation did not result in significant accumulation of DNA methylation alterations. However, extended dose fractionations changed DNA methylation profiles and induced thousands of differentially methylated positions, specifically in enhancer regions, sites involved in alternative splicing and in repetitive regions. Radiation induced dose-dependent morphological and proliferative alterations of the cells as a consequence of the radiation exposure. Conclusions DNA methylation alterations of sites with regulatory functions in proliferation and differentiation were identified, which may reflect cellular response to radiation stress through epigenetic reprogramming and differentiation cues.
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| 16. |
- Danielsson, Anna, 1973, et al.
(författare)
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MethPed: a DNA methylation classifier tool for the identification of pediatric brain tumor subtypes
- 2015
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7083 .- 1868-7075. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Classification of pediatric tumors into biologically defined subtypes is challenging, and multifaceted approaches are needed. For this aim, we developed a diagnostic classifier based on DNA methylation profiles. Results: Methylation data generated by the Illumina Infinium HumanMethylation 450 BeadChip arrays were downloaded from the Gene Expression Omnibus (n = 472). Using the data, we built MethPed, which is a multiclass random forest algorithm, based on DNA methylation profiles from nine subgroups of pediatric brain tumors. DNA from 18 regional samples was used to validate MethPed. MethPed was additionally applied to a set of 28 publically available tumors with the heterogeneous diagnosis PNET. MethPed could successfully separate individual histology tumor types at a very high accuracy (kappa = 0.98). Analysis of a regional cohort demonstrated the clinical benefit of MethPed, as confirmation of diagnosis of tumors with clear histology but also identified possible differential diagnoses in tumors with complicated and mixed type morphology. Conclusions: We demonstrate the utility of methylation profiling of pediatric brain tumors and offer MethPed as an easy-to-use toolbox that allows researchers and clinical diagnosticians to test single samples as well as large cohorts for subclass prediction of pediatric brain tumors. This will immediately aid clinical practice and importantly increase our molecular knowledge of these tumors for further therapeutic development.
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| 17. |
- Elbere, Ilze, et al.
(författare)
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Significantly altered peripheral blood cell DNA methylation profile as a result of immediate effect of metformin use in healthy individuals
- 2018
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7083 .- 1868-7075. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Metformin is a widely prescribed antihyperglycemic agent that has been also associated with multiple therapeutic effects in various diseases, including several types of malignancies. There is growing evidence regarding the contribution of the epigenetic mechanisms in reaching metformin's therapeutic goals; however, the effect of metformin on human cells in vivo is not comprehensively studied. The aim of our study was to examine metformin-induced alterations of DNA methylation profiles in white blood cells of healthy volunteers, employing a longitudinal study design.Results: Twelve healthy metformin-naive individuals where enrolled in the study. Genome-wide DNA methylation pattern was estimated at baseline, 10h and 7days after the start of metformin administration. The whole-genome DNA methylation analysis in total revealed 125 differentially methylated CpGs, of which 11 CpGs and their associated genes with the most consistent changes in the DNA methylation profile were selected: POFUT2, CAMKK1, EML3, KIAA1614, UPF1, MUC4, LOC727982, SIX3, ADAM8, SNORD12B, VPS8, and several differentially methylated regions as novel potential epigenetic targets of metformin. The main functions of the majority of top-ranked differentially methylated loci and their representative cell signaling pathways were linked to the well-known metformin therapy targets: regulatory processes of energy homeostasis, inflammatory responses, tumorigenesis, and neurodegenerative diseases.Conclusions: Here we demonstrate for the first time the immediate effect of short-term metformin administration at therapeutic doses on epigenetic regulation in human white blood cells. These findings suggest the DNA methylation process as one of the mechanisms involved in the action of metformin, thereby revealing novel targets and directions of the molecular mechanisms underlying the various beneficial effects of metformin.Trial registrationEU Clinical Trials Register, 2016-001092-74. Registered 23 March 2017, https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-001092-74/LV.
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| 18. |
- Fernandez-Sanles, Alba, et al.
(författare)
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DNA methylation biomarkers of myocardial infarction and cardiovascular disease
- 2021
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Ingår i: Clinical Epigenetics. - : BioMed Central (BMC). - 1868-7083 .- 1868-7075. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: The epigenetic landscape underlying cardiovascular disease (CVD) is not completely understood and the clinical value of the identified biomarkers is still limited. We aimed to identify differentially methylated loci associated with acute myocardial infarction (AMI) and assess their validity as predictive and causal biomarkers.Results: We designed a case-control, two-stage, epigenome-wide association study on AMI (n(discovery) = 391, n(validation) = 204). DNA methylation was assessed using the Infinium MethylationEPIC BeadChip. We performed a fixed-effects meta-analysis of the two samples. 34 CpGs were associated with AMI. Only 12 of them were available in two independent cohort studies (n similar to 1800 and n similar to 2500) with incident coronary and cardiovascular disease (CHD and CVD, respectively). The Infinium HumanMethylation450 BeadChip was used in those two studies. Four of the 12 CpGs were validated in association with incident CHD: AHRR-mapping cg05575921, PTCD2-mapping cg25769469, intergenic cg21566642 and MPO-mapping cg04988978. We then assessed whether methylation risk scores based on those CpGs improved the predictive capacity of the Framingham risk function, but they did not. Finally, we aimed to study the causality of those associations using a Mendelian randomization approach but only one of the CpGs had a genetic influence and therefore the results were not conclusive.Conclusions: We have identified 34 CpGs related to AMI. These loci highlight the relevance of smoking, lipid metabolism, and inflammation in the biological mechanisms related to AMI. Four were additionally associated with incident CHD and CVD but did not provide additional predictive information.
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| 19. |
- Ferreyra Vega, Sandra, et al.
(författare)
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DNA methylation profiling for molecular classification of adult diffuse lower-grade gliomas.
- 2021
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Ingår i: Clinical Epigenetics. - : Springer Nature. - 1868-7083 .- 1868-7075. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: DNA methylation profiling has facilitated and improved the classification of a wide variety of tumors of the central nervous system. In this study, we investigated the potential utility of DNA methylation profiling to achieve molecular diagnosis in adult primary diffuse lower-grade glioma (dLGG) according to WHO 2016 classification system. We also evaluated whether methylation profiling could provide improved molecular characterization and identify prognostic differences beyond the classical histological WHO grade together with IDH mutation status and 1p/19q codeletion status. All patients diagnosed with dLGG in the period 2007-2016 from the Västra Götaland region in Sweden were assessed for inclusion in the study.RESULTS: A total of 166 dLGG cases were subjected for genome-wide DNA methylation analysis. Of these, 126 (76%) were assigned a defined diagnostic methylation class with a class prediction score ≥ 0.84 and subclass score ≥ 0.50. The assigned methylation classes were highly associated with their IDH mutation status and 1p/19q codeletion status. IDH-wildtype gliomas were further divided into subgroups with distinct molecular features.CONCLUSION: The stratification of the patients by methylation profiling was as effective as the integrated WHO 2016 molecular reclassification at predicting the clinical outcome of the patients. Our study shows that DNA methylation profiling is a reliable and robust approach for the classification of dLGG into molecular defined subgroups, providing accurate detection of molecular markers according to WHO 2016 classification.
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| 20. |
- García-Calzón, Sonia, et al.
(författare)
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Diabetes medication associates with DNA methylation of metformin transporter genes in the human liver
- 2017
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7075 .- 1868-7083. ; 9:1, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Given that metformin is the most common pharmacological therapy for type 2 diabetes, understanding the function of this drug is of great importance. Hepatic metformin transporters are responsible for the pharmacologic action of metformin. However, epigenetics in genes encoding metformin transporters has not been fully elucidated. We examined the DNA methylation of these genes in the liver of subjects with type 2 diabetes and tested whether epigenetic alterations associate with diabetes medication, i.e., metformin or insulin plus metformin treatment. Results: DNA methylation in OCT1 encoded by SLC22A1, OCT3 encoded by SLC22A3, and MATE1 encoded by SLC47A1 was assessed in the human liver. Lower average and promoter DNA methylation of SLC22A1, SLC22A3, and SLC47A1 was found in diabetic subjects receiving just metformin, compared to those who took insulin plus metformin or no diabetes medication. Moreover, diabetic subjects receiving just metformin had a similar DNA methylation pattern in these genes compared to non-diabetic subjects. Notably, DNA methylation was also associated with gene expression, glucose levels, and body mass index, i.e., higher SLC22A3 methylation was related to lower SLC22A3 expression and to insulin plus metformin treatment, higher fasting glucose levels and higher body mass index. Importantly, metformin treatment did also directly decrease DNA methylation of SLC22A1 in hepatocytes cultured in vitro. Conclusions: Our study supports that metformin decreases DNA methylation of metformin transporter genes in the human liver. Moreover, higher methylation levels in these genes associate with hyperglycaemia and obesity.
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| 21. |
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| 22. |
- Guerrero-Bosagna, Carlos, 1975-, et al.
(författare)
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Globalization, climate change, and transgenerational epigenetic inheritance: will our descendants be at risk?
- 2015
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Ingår i: Clinical Epigenetics. - : BioMed Central. - 1868-7083 .- 1868-7075. ; 7:8
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Tidskriftsartikel (refereegranskat)abstract
- Transgenerational epigenetic inheritance has gained increased attention due to the possibility that exposure to environmental contaminants induce diseases that propagate across generations through epigenomic alterations in gametes. In laboratory animals,exposure to environmental toxicants such as fungicides, pesticides, or plastic compounds has been shown to produce abnormal reproductive or metabolic phenotypes that are transgenerationally transmitted. Human exposures to environmental toxicants have increased due to industrialization and globalization, as well as the incidence of diseases shown to be transgenerationally transmitted in animal models. This new knowledge poses an urgent call to study transgenerational consequences of current human exposures to environmental toxicants.
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| 23. |
- Hjort, Line, et al.
(författare)
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36 h fasting of young men influences adipose tissue DNA methylation of LEP and ADIPOQ in a birth weight-dependent manner
- 2017
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7075 .- 1868-7083. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Subjects born with low birth weight (LBW) display a more energy-conserving response to fasting compared with normal birth weight (NBW) subjects. However, the molecular mechanisms explaining these metabolic differences remain unknown. Environmental influences may dynamically affect epigenetic marks, also in postnatal life. Here, we aimed to study the effects of short-term fasting on leptin (LEP) and adiponectin (ADIPOQ) DNA methylation and gene expression in subcutaneous adipose tissue (SAT) from subjects with LBW and NBW. Methods: Twenty-one young LBW men and 18 matched NBW controls were studied during 36 h fasting. Eight subjects from each group completed a control study (overnight fast). We analyzed SAT LEP and ADIPOQ methylation (Epityper MassARRAY), gene expression (q-PCR), and adipokine plasma levels. Results: After overnight fast (control study), LEP and ADIPOQ DNA methylation levels were higher in LBW compared to those in NBW subjects (p ≤ 0.03) and increased with 36 h fasting in NBW subjects only (p ≤ 0.06). Both LEP and ADIPOQ methylation levels were positively associated with total body fat percentage (p ≤ 0.05). Plasma leptin levels were higher in LBW versus NBW subjects after overnight fasting (p = 0.04) and decreased more than threefold in both groups after 36 h fasting (p ≤ 0.0001). Conclusions: This is the first study to demonstrate that fasting induces changes in DNA methylation. This was shown in LEP and ADIPOQ promoters in SAT among NBW but not LBW subjects. The altered epigenetic flexibility in LBW subjects might contribute to their differential response to fasting, adipokine levels, and increased risk of metabolic disease.
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| 24. |
- Huoman, Johanna, et al.
(författare)
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Combined prenatal Lactobacillus reuteri and omega-3 supplementation synergistically modulates DNA methylation in neonatal T helper cells
- 2021
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Ingår i: Clinical Epigenetics. - : BMC. - 1868-7083 .- 1868-7075. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundEnvironmental exposures may alter DNA methylation patterns of T helper cells. As T helper cells are instrumental for allergy development, changes in methylation patterns may constitute a mechanism of action for allergy preventive interventions. While epigenetic effects of separate perinatal probiotic or omega -3 fatty acid supplementation have been studied previously, the combined treatment has not been assessed. We aimed to investigate epigenome-wide DNA methylation patterns from a sub-group of children in an on-going randomised double-blind placebo-controlled allergy prevention trial using pre- and postnatal combined Lactobacillus reuteri and omega -3 fatty acid treatment. To this end,>866000 CpG sites (MethylationEPIC 850K array) in cord blood CD4+ T cells were examined in samples from all four study arms (double-treatment: n=18, single treatments: probiotics n=16, omega -3 n=15, and double placebo: n=14). Statistical and bioinformatic analyses identified treatment-associated differentially methylated CpGs and genes, which were used to identify putatively treatment-induced network modules. Pathway analyses inferred biological relevance, and comparisons were made to an independent allergy data set.ResultsComparing the active treatments to the double placebo group, most differentially methylated CpGs and genes were hypermethylated, possibly suggesting induction of transcriptional inhibition. The double-treated group showed the largest number of differentially methylated CpGs, of which many were unique, suggesting synergy between interventions. Clusters within the double-treated network module consisted of immune-related pathways, including T cell receptor signalling, and antigen processing and presentation, with similar pathways revealed for the single-treatment modules. CpGs derived from differential methylation and network module analyses were enriched in an independent allergy data set, particularly in the double-treatment group, proposing treatment-induced DNA methylation changes as relevant for allergy development.ConclusionPrenatal L. reuteri and/or omega -3 fatty acid treatment results in hypermethylation and affects immune- and allergy-related pathways in neonatal T helper cells, with potentially synergistic effects between the interventions and relevance for allergic disease. Further studies need to address these findings on a transcriptional level, and whether the results associate to allergy development in the children. Understanding the role of DNA methylation in regulating effects of perinatal probiotic and omega -3 interventions may provide essential knowledge in the development of efficacious allergy preventive strategies.Trial registration ClinicalTrials.gov, ClinicalTrials.gov-ID: NCT01542970. Registered 27th of February 2012-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01542970.
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| 25. |
- Karlsson, Ida K., et al.
(författare)
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Epigenome-wide association study of level and change in cognitive abilities from midlife through late life
- 2021
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Ingår i: Clinical Epigenetics. - : Springer Nature. - 1868-7083 .- 1868-7075. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epigenetic mechanisms are important in aging and may be involved in late-life changes in cognitive abilities. We conducted an epigenome-wide association study of leukocyte DNA methylation in relation to level and change in cognitive abilities, from midlife through late life in 535 Swedish twins. Results: Methylation levels were measured with the Infinium Human Methylation 450 K or Infinium MethylationEPIC array, and all sites passing quality control on both arrays were selected for analysis (n = 250,816). Empirical Bayes estimates of individual intercept (age 65), linear, and quadratic change were obtained from latent growth curve models of cognitive traits and used as outcomes in linear regression models. Significant sites (p < 2.4 × 10–7) were followed up in between-within twin pair models adjusting for familial confounding and full-growth modeling. We identified six significant associations between DNA methylation and level of cognitive abilities at age 65: cg18064256 (PPP1R13L) with processing speed and spatial ability; cg04549090 (NRXN3) with spatial ability; cg09988380 (POGZ), cg25651129 (-), and cg08011941 (ENTPD8) with working memory. The genes are involved in neuroinflammation, neuropsychiatric disorders, and ATP metabolism. Within-pair associations were approximately half that of between-pair associations across all sites. In full-growth curve models, associations between DNA methylation and cognitive level at age 65 were of small effect sizes, and associations between DNA methylation and longitudinal change in cognitive abilities of very small effect sizes. Conclusions: Leukocyte DNA methylation was associated with level, but not change in cognitive abilities. The associations were substantially attenuated in within-pair analyses, indicating they are influenced in part by genetic factors.
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