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Effect of adding B-vitamins to vitamin D and calcium supplementation on CpG methylation of epigenetic aging markers.
Obeid, R, Hübner, U, Bodis, M, Graeber, S, Geisel, J
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2018;(4):411-417
Abstract
BACKGROUND AND AIM B-vitamins may influence DNA methylation. We studied the effects of vitamin D + Ca + B versus D + Ca on epigenetic age markers and biological age. METHODS AND RESULTS Participants (mean ± SD of age = 68.4 ± 10.1 years) were randomized to receive 1200 IE vitamin D3 plus 800 mg Ca-carbonate alone (n = 31) or with 0.5 mg B9, 50 mg B6, and 0.5 mg B12 (n = 32). The CpG methylation of 3 genes (ASPA, ITGA2B, and PDE4C) and the changes in methylation were compared between the groups after 1 year. The changes of ASPA methylation from baseline were higher in the D + Ca + B than in the D + Ca group (1.40 ± 4.02 vs. -0.96 ± 5.12, respectively; p = 0.046, adjusted for age, sex, and baseline methylation). The changes in PDE4C from baseline were slightly higher in the D + Ca + B group (1.95 ± 3.57 vs. 0.22 ± 3.57; adjusted p = 0.062). Methylation of ITGA2B and its changes from baseline were not different between the intervention groups. Sex-adjusted odds ratio of accelerated aging (chronological age < biological age at 1 year) was 5.26 (95% confidence interval 1.51-18.28) in the D + Ca + B compared with the D + Ca group. Accelerated aging in both groups was associated with younger age. In the D + Ca + B group, it was additionally associated with lower baseline homocysteine. CONCLUSIONS Vitamin D + Ca + B and D + Ca differentially affected epigenetic age markers, although the effect size appeared to be small after 1 year. B-vitamins effect in young subjects with low homocysteine requires further investigation. ClinicalTrials.gov ID: NCT02586181.
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Impact of polyunsaturated and saturated fat overfeeding on the DNA-methylation pattern in human adipose tissue: a randomized controlled trial.
Perfilyev, A, Dahlman, I, Gillberg, L, Rosqvist, F, Iggman, D, Volkov, P, Nilsson, E, Risérus, U, Ling, C
The American journal of clinical nutrition. 2017;(4):991-1000
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Abstract
Background: Dietary fat composition can affect ectopic lipid accumulation and, thereby, insulin resistance. Diets that are high in saturated fatty acids (SFAs) or polyunsaturated fatty acids (PUFAs) have different metabolic responses.Objective: We investigated whether the epigenome of human adipose tissue is affected differently by dietary fat composition and general overfeeding in a randomized trial.Design: We studied the effects of 7 wk of excessive SFA (n = 17) or PUFA (n = 14) intake (+750 kcal/d) on the DNA methylation of ∼450,000 sites in human subcutaneous adipose tissue. Both diets resulted in similar body weight increases. We also combined the data from the 2 groups to examine the overall effect of overfeeding on the DNA methylation in adipose tissue.Results: The DNA methylation of 4875 Cytosine-phosphate-guanine (CpG) sites was affected differently between the 2 diets. Furthermore, both the SFA and PUFA diets increased the mean degree of DNA methylation in adipose tissue, particularly in promoter regions. However, although the mean methylation was changed in 1797 genes [e.g., alpha-ketoglutarate dependent dioxygenase (FTO), interleukin 6 (IL6), insulin receptor (INSR), neuronal growth regulator 1 (NEGR1), and proopiomelanocortin (POMC)] by PUFAs, only 125 genes [e.g., adiponectin, C1Q and collagen domain containing (ADIPOQ)] were changed by SFA overfeeding. In addition, the SFA diet significantly altered the expression of 28 transcripts [e.g., acyl-CoA oxidase 1 (ACOX1) and FAT atypical cadherin 1 (FAT1)], whereas the PUFA diet did not significantly affect gene expression. When the data from the 2 diet groups were combined, the mean methylation of 1444 genes, including fatty acid binding protein 1 (FABP1), fatty acid binding protein 2 (FABP2), melanocortin 2 receptor (MC2R), MC3R, PPARG coactivator 1 α (PPARGC1A), and tumor necrosis factor (TNF), was changed in adipose tissue by overfeeding. Moreover, the baseline DNA methylation of 12 CpG sites that was annotated to 9 genes [e.g., mitogen-activated protein kinase 7 (MAPK7), melanin concentrating hormone receptor 1 (MCHR1), and splicing factor SWAP homolog (SFRS8)] was associated with the degree of weight increase in response to extra energy intake.Conclusions: SFA overfeeding and PUFA overfeeding induce distinct epigenetic changes in human adipose tissue. In addition, we present data that suggest that baseline DNA methylation can predict weight increase in response to overfeeding in humans. This trial was registered at clinicaltrials.gov as NCT01427140.
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Cholesterol lowering treatment restores blood global DNA methylation in chronic kidney disease (CKD) patients.
Zinellu, A, Sotgia, S, Sotgiu, E, Assaretti, S, Baralla, A, Mangoni, AA, Satta, AE, Carru, C
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2017;(9):822-829
Abstract
BACKGROUND AND AIMS Chronic kidney disease (CKD) is characterized by increased oxidative stress (OS). In consideration of the well-known link between OS and DNA methylation we assessed DNA methylcytosine (mCyt) concentrations in CKD patients at baseline and during cholesterol lowering treatment. METHODS AND RESULTS DNA methylation and OS indices (malonyldialdehyde, MDA; allantoin/uric acid ratio, All/UA) were measured in 30 CKD patients randomized to three cholesterol lowering regimens for 12 months (simvastatin 40 mg/day, ezetimibe/simvastatin 10/20 mg/day, or ezetimibe/simvastatin 10/40 mg/day) and 30 age- and sex-matched healthy controls. DNA methylation was significantly lower in CKD patients vs. controls (4.06 ± 0.20% vs. 4.27 ± 0.17% mCyt, p = 0.0001). Treatment significantly increased mCyt DNA concentrations in all patients (4.06 ± 0.04% at baseline; 4.12 ± 0.03% at 4 months; 4.17 ± 0.03% at 8 months; and 4.20 ± 0.02% at 12 months, p = 0.0001 for trend). A trend for a greater effect on DNA methylation was observed with combined treatment ezetimibe/simvastatin 10/40 mg/day (+5.2% after one year treatment). The treatment-associated mCyt increase was significantly correlated with the concomitant reduction in MDA concentrations and All/AU ratios. CONCLUSION Our results demonstrate that CKD patients have a lower degree of DNA methylation and that cholesterol lowering treatment restores mCyt DNA concentrations to levels similar to healthy controls. The treatment-associated increase in DNA methylation is correlated with a concomitant reduction in OS markers. The study was registered at clinicaltrials.gov (NCT00861731).
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Comparative epigenomics: a powerful tool to understand the evolution of DNA methylation.
Zhong, X
The New phytologist. 2016;(1):76-80
Abstract
Understanding how developmental and functional complexity of organisms evolves is a longstanding challenge in biology. Genetic mutation has long been thought to be the cause of biological complexity. However, increasing evidence indicates that epigenetic variation provides a parallel path for the evolution of biological complexity. Cytosine DNA methylation, the addition of a chemical mark on DNA, is a conserved and essential gene regulatory mechanism. Recent studies have greatly advanced our understanding of the DNA methylation landscapes and key regulatory components across many species. In this review, I summarize recent advances in understanding DNA methylation from an evolutionary perspective. Using comparative approaches, I highlight the conservation and divergence of DNA methylation patterns and regulatory machinery in plants and other eukaryotic organisms.
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Cesarean delivery and hematopoietic stem cell epigenetics in the newborn infant: implications for future health?
Almgren, M, Schlinzig, T, Gomez-Cabrero, D, Gunnar, A, Sundin, M, Johansson, S, Norman, M, Ekström, TJ
American journal of obstetrics and gynecology. 2014;(5):502.e1-8
Abstract
OBJECTIVE Cesarean section (CS) has been associated with a greater risk for asthma, diabetes, and cancer later in life. Although elective CS continues to rise, it is unclear whether and how it may contribute to compromised future health. Our aim was to investigate the influence of mode of delivery on the epigenetic state in neonatal hematopoietic stem cells. STUDY DESIGN This was an observational study of 64 healthy, singleton, newborn infants (33 boys) born at term. Cord blood was sampled after elective CS (n = 27) and vaginal delivery. Global deoxyribonucleic acid (DNA) methylation in hematopoietic stem cells (CD34+) was determined by luminometric methylation assay, and genome-wide, locus-specific DNA methylation analysis was performed by Illumina Infinium 450K (Illumina, San Diego, CA), validated by bisulfite-pyrosequencing. RESULTS CD34+ cells from infants delivered by CS were globally more DNA methylated (+2%) than DNA from infants delivered vaginally (P = .02). In relation to mode of delivery, a locus-specific analysis identified 343 loci with a difference in DNA methylation of 10% or greater (P < .01). A majority of the differentially methylated loci in neonatal CD34+ cells (76%) were found to be hypermethylated after vaginal delivery. In these infants, the degree of DNA methylation in 3 loci correlated to the duration of labor. The functional relevance of differentially methylated loci involved processes such as immunoglobulin biosynthetic process, regulation of glycolysis and ketone metabolism, and regulation of the response to food. CONCLUSION A possible interpretation is that mode of delivery affects the epigenetic state of neonatal hematopoietic stem cells. Given the functional relevance indicated, our findings may have important implications for health and disease in later life.
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Epigenetic control of skin differentiation genes by phytocannabinoids.
Pucci, M, Rapino, C, Di Francesco, A, Dainese, E, D'Addario, C, Maccarrone, M
British journal of pharmacology. 2013;(3):581-91
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Abstract
BACKGROUND AND PURPOSE Endocannabinoid signalling has been shown to have a role in the control of epidermal physiology, whereby anandamide is able to regulate the expression of skin differentiation genes through DNA methylation. Here, we investigated the possible epigenetic regulation of these genes by several phytocannabinoids, plant-derived cannabinoids that have the potential to be novel therapeutics for various human diseases. EXPERIMENTAL APPROACH The effects of cannabidiol, cannabigerol and cannabidivarin on the expression of skin differentiation genes keratins 1 and 10, involucrin and transglutaminase 5, as well as on DNA methylation of keratin 10 gene, were investigated in human keratinocytes (HaCaT cells). The effects of these phytocannabinoids on global DNA methylation and the activity and expression of four major DNA methyltransferases (DNMT1, 3a, 3b and 3L) were also examined. KEY RESULTS Cannabidiol and cannabigerol significantly reduced the expression of all the genes tested in differentiated HaCaT cells, by increasing DNA methylation of keratin 10 gene, but cannabidivarin was ineffective. Remarkably, cannabidiol reduced keratin 10 mRNA through a type-1 cannabinoid (CB1 ) receptor-dependent mechanism, whereas cannabigerol did not affect either CB1 or CB2 receptors of HaCaT cells. In addition, cannabidiol, but not cannabigerol, increased global DNA methylation levels by selectively enhancing DNMT1 expression, without affecting DNMT 3a, 3b or 3L. CONCLUSIONS AND IMPLICATIONS These findings show that the phytocannabinoids cannabidiol and cannabigerol are transcriptional repressors that can control cell proliferation and differentiation. This indicates that they (especially cannabidiol) have the potential to be lead compounds for the development of novel therapeutics for skin diseases.
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Alterations in sperm DNA methylation patterns at imprinted loci in two classes of infertility.
Hammoud, SS, Purwar, J, Pflueger, C, Cairns, BR, Carrell, DT
Fertility and sterility. 2010;(5):1728-33
Abstract
OBJECTIVE To evaluate the associations between proper protamine incorporation and DNA methylation at imprinted loci. DESIGN Experimental research study. SETTING Research laboratory. PATIENT(S): Three populations were tested-abnormal protamine patients, oligozoospermic patients, and fertile donors. INTERVENTION(S): The CpG methylation patterns were examined at seven imprinted loci sequenced: LIT1, MEST, SNRPN, PLAGL1, PEG3, H19, and IGF2. MAIN OUTCOME MEASURE(S): The DNA methylation patterns were analyzed using bisulfite sequencing. The percentage of methylation was compared between fertile and infertile patients displaying abnormal protamination. RESULT(S): At six of the seven imprinted genes, the overall DNA methylation patterns at their respective differentially methylated regions were significantly altered in both infertile patient populations. When comparing the severity of methylation alterations among infertile patients, the oligozoospermic patients were significantly affected at mesoderm-specific transcript (MEST), whereas abnormal protamine patients were affected at KCNQ1, overlapping transcript 1 (LIT1), and at small nuclear ribonucleoprotein polypeptide N (SNRPN). CONCLUSION(S): Patients with male factor infertility had significantly increased methylation alteration at six of seven imprinted loci tested, with differences in significance observed between oligozoospermic and abnormal protamine patients. This could suggest that risk of transmission of epigenetic alterations may be different with diagnoses. However, this study does not provide a causal link for epigenetic inheritance of imprinting diseases, but does show significant association between male factor infertility and alterations in sperm DNA methylation at imprinted loci.