Longitudinal genome-wide DNA methylation changes in response to kidney failure replacement therapy

AbstractChronic kidney disease (CKD) is an emerging public health priority associated with high mortality rates and demanding treatment regimens, including life-style changes, medications or even dialysis or renal transplantation. Unavoidably, the uremic milieu disturbs homeostatic processes such as DNA methylation and other vital gene regulatory mechanisms. Here, we aimed to investigate how dialysis or kidney transplantation modifies the epigenome-wide methylation signature over 12 months of treatment. We used the Infinium HumanMethylation450 BeadChip on whole blood samples from CKD-patients undergoing either dialysis (n = 11) or kidney transplantation (n = 12) and 24 age- and sex-matched population-based controls. At baseline, comparison between patients and controls identified several significant (PFDR < 0.01) CpG methylation differences in genes with functions relevant to inflammation, cellular ageing and vascular calcification. Following 12 months, the global DNA methylation pattern of patients approached that seen in the control group. Notably, 413 CpG sites remained differentially methylated at follow-up in both treatment groups compared to controls. Together, these data indicate that the uremic milieu drives genome-wide methylation changes that are partially reversed with kidney failure replacement therapy. Differentially methylated CpG sites unaffected by treatment may be of particular interest as they could highlight candidate genes for kidney disease per se.

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DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures

Clinical Epigenetics ◽

10.1186/s13148-020-00957-8 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Monica del C. Gomez-Alonso ◽

Anja Kretschmer ◽

Rory Wilson ◽

Liliane Pfeiffer ◽

Ville Karhunen ◽

...

Keyword(s):

Dna Methylation ◽

Lipid Metabolism ◽

Population Based ◽

Total Serum ◽

Resonance Spectroscopy ◽

Metabolic Disturbances ◽

Cpg Sites ◽

Gene Transcripts

Abstract Background The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances. Results We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10−10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations. Conclusion Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.

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DNA methylation mediates the association between breastfeeding and early-life growth trajectories

Clinical Epigenetics ◽

10.1186/s13148-021-01209-z ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Laurent Briollais ◽

Denis Rustand ◽

Catherine Allard ◽

Yanyan Wu ◽

Jingxiong Xu ◽

...

Keyword(s):

Dna Methylation ◽

Signaling Pathway ◽

Exclusive Breastfeeding ◽

Child Growth ◽

Postnatal Period ◽

Overweight And Obesity ◽

Breastfeeding Duration ◽

Ampk Signaling ◽

Cpg Sites ◽

Genome Wide

Abstract Background The role of breastfeeding in modulating epigenetic factors has been suggested as a possible mechanism conferring its benefits on child development but it lacks evidence. Using extensive DNA methylation data from the ALSPAC child cohort, we characterized the genome-wide landscape of DNA methylation variations associated with the duration of exclusive breastfeeding and assessed whether these variations mediate the association between exclusive breastfeeding and BMI over different epochs of child growth. Results Exclusive breastfeeding elicits more substantial DNA methylation variations during infancy than at other periods of child growth. At the genome-wide level, 13 CpG sites in girls (miR-21, SNAPC3, ATP6V0A1, DHX15/PPARGC1A, LINC00398/ALOX5AP, FAM238C, NATP/NAT2, CUX1, TRAPPC9, OSBPL1A, ZNF185, FAM84A, PDPK1) and 2 CpG sites in boys (IL16 and NREP), mediate the association between exclusive breastfeeding and longitudinal BMI. We found enrichment of CpG sites located within miRNAs and key pathways (AMPK signaling pathway, insulin signaling pathway, endocytosis). Overall DNA methylation variation corresponding to 3 to 5 months of exclusive breastfeeding was associated with slower BMI growth the first 6 years of life compared to no breastfeeding and in a dose–response manner with exclusive breastfeeding duration. Conclusions Our study confirmed the early postnatal period as a critical developmental period associated with substantial DNA methylation variations, which in turn could mitigate the development of overweight and obesity from infancy to early childhood. Since an accelerated growth during these developmental periods has been linked to the development of sustained obesity later in life, exclusive breastfeeding could have a major role in preventing the risks of overweight/obesity and children and adults through DNA methylation mechanisms occurring early in life.

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Chicken cecal DNA methylome alteration in the response to Salmonella enterica serovar Enteritidis inoculation

10.21203/rs.3.rs-20344/v2 ◽

2020 ◽

Author(s):

Yuanmei Wang ◽

Liying Liu ◽

Min Li ◽

Lili Lin ◽

Pengcheng Su ◽

...

Keyword(s):

Dna Methylation ◽

Signaling Pathway ◽

Salmonella Enterica ◽

Methylation Profile ◽

Control Group ◽

Poultry Production ◽

Salmonella Enterica Serovar Enteritidis ◽

Genome Wide ◽

Differentially Methylated Genes ◽

Dna Methylation Profile

Abstract Background: Salmonella enterica serovar Enteritidis (SE) is one of the pathogenic bacteria, which affects poultry production and poses a severe threat to public health. Chicken meat and eggs are the main sources of human salmonellosis. DNA methylation is involved in regulatory processes including gene expression, chromatin structure and genomic imprinting. To understand the methylation regulation in the response to SE inoculation in chicken, the genome-wide DNA methylation profile following SE inoculation was analyzed through whole-genome bisulfite sequencing in the current study.Results: There were 185,362,463 clean reads and 126,098,724 unique reads in the control group, and 180,530,750 clean Reads and 126,782,896 unique reads in the inoculated group. The methylation density in the gene body was higher than that in the upstream and downstream regions of the gene. There were 8,946 differentially methylated genes (3,639 hypo-methylated genes, 5,307 hyper-methylated genes) obtained between inoculated and control groups. Methylated genes were mainly enriched in immune-related Gene Ontology (GO) terms and metabolic process terms. Cytokine-cytokine receptor interaction, TGF-beta signaling pathway, FoxO signaling pathway, Wnt signaling pathway and several metabolism-related pathways were significantly enriched. The density of differentially methylated cytosines in miRNAs was the highest. HOX genes were widely methylated.Conclusions: The genome-wide DNA methylation profile in the response to SE inoculation in chicken was analyzed. SE inoculation promoted the DNA methylation in the chicken cecum and caused methylation alteration in immune- and metabolic- related genes. Wnt signal pathway, miRNAs and HOX gene family may play crucial roles in the methylation regulation of SE inoculation in chicken. The findings herein will deepen the understanding of epigenetic regulation in the response to SE inoculation in chicken.

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Abstract P098: An Epigenome-wide Study of Obesity in African American Youth and Young Adults: Novel Findings, Replication in Neutrophils and Relationship With Gene Expression

Circulation ◽

10.1161/circ.135.suppl_1.p098 ◽

2017 ◽

Vol 135 (suppl_1) ◽

Author(s):

Xiaoling Wang ◽

Yue Pan ◽

Haidong Zhu ◽

Guang Hao ◽

Xin Wang ◽

...

Keyword(s):

Gene Expression ◽

Older Adults ◽

Dna Methylation ◽

Young Adults ◽

Methylation Data ◽

Middle Aged ◽

Cpg Sites ◽

Genome Wide ◽

Obesity Status ◽

Youth And Young Adults

Background: Several large-scale epigenome wide association studies on obesity-related DNA methylation changes have been published and in total identified 46 CpG sites. These studies were conducted in middle-aged and older adults of Caucasians and African Americans (AAs) using leukocytes. To what extend these signals are independent of cell compositions as well as to what extend they may influence gene expression have not been systematically investigated. Furthermore, the high prevalence of obesity comorbidities in middle-aged or older population may hide or bias obesity itself related DNA methylation changes. Methods: In this study of healthy AA youth and young adults, genome wide DNA methylation data from leukocytes were obtained from three independent studies: EpiGO study (96 obese cases vs. 92 lean controls, aged 14-21, 50% females, test of interest is obesity status), LACHY study (284 participants from general population, aged 14-18, 50% females, test of interest is BMI), and Georgia Stress and Heart study (298 participants from general population, aged 18-38, 52% females, test of interest is BMI) using the Infinium HumanMethylation450 BeadChip. Genome wide DNA methylation data from purified neutrophils as well as genome wide gene expression data from leukocytes using Illumina HT12 V4 array were also obtained for the EpiGO samples. Results: The meta-analysis on the 3 cohorts identified 76 obesity related CpG sites in leukocytes with p<1х10 -7 . Out of the 46 previously identified CpG sites, 36 can be replicated in this AA youth and young adult sample with same direction and p<0.05. Out of the 107 CpG sites including the 36 replicated ones and the 71 newly identified ones, 71 CpG sites (66%) had their relationship with obesity replicated in purified neutrophils (p<0.05). The analysis on the cis regulation of the 107 CpG sites on gene expression showed that 59 CpG sites had at least one gene within 250kb having expression difference between obese cases and lean controls. Furthermore, out of the 59 CpG sites, 6 showed significantly negative correlations and 1 showed significantly positive correlation with the differentially expressed genes. These CpG sites located in SOCS3, CISH, ABCG1, PIM3 and PTGDS genes. Conclusion: In this study of AA youth and young adults, we identified novel CpG sites associated with obesity and replicated majority of the CpG sites previously identified in middle-aged and older adults. For the first time, we showed that majority of the obesity related CpG sites identified from leukocytes are not driven by cell compositions and provided the direct link between DNA methylation-gene expression-obesity status for 7 CpG sites in 5 genes.

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Changes in DNA Methylation and Gene Expression of Insulin and Obesity-Related Gene PIK3R1 after Roux-en-Y Gastric Bypass

International Journal of Molecular Sciences ◽

10.3390/ijms21124476 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4476

Author(s):

Marcela A S Pinhel ◽

Natália Y Noronha ◽

Carolina F Nicoletti ◽

Vanessa AB Pereira ◽

Bruno AP de Oliveira ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Weight Loss ◽

Gastric Bypass ◽

Related Gene ◽

Cpg Sites ◽

Genome Wide ◽

Genetically Determined ◽

Methylation Patterns ◽

Weight Loss Interventions

Weight regulation and the magnitude of weight loss after a Roux-en-Y gastric bypass (RYGB) can be genetically determined. DNA methylation patterns and the expression of some genes can be altered after weight loss interventions, including RYGB. The present study aimed to evaluate how the gene expression and DNA methylation of PIK3R1, an obesity and insulin-related gene, change after RYGB. Blood samples were obtained from 13 women (35.9 ± 9.2 years) with severe obesity before and six months after surgical procedure. Whole blood transcriptome and epigenomic patterns were assessed by microarray-based, genome-wide technologies. A total of 1966 differentially expressed genes were identified in the pre- and postoperative periods of RYGB. From these, we observed that genes involved in obesity and insulin pathways were upregulated after surgery. Then, the PIK3R1 gene was selected for further RT-qPCR analysis and cytosine-guanine nucleotide (CpG) sites methylation evaluation. We observed that the PI3KR1 gene was upregulated, and six DNA methylation CpG sites were differently methylated after bariatric surgery. In conclusion, we found that RYGB upregulates genes involved in obesity and insulin pathways.

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Genome-wide DNA methylation profile of early-onset endometrial cancer: its correlation with genetic aberrations and comparison with late-onset endometrial cancer

Carcinogenesis ◽

10.1093/carcin/bgz046 ◽

2019 ◽

Vol 40 (5) ◽

pp. 611-623 ◽

Cited By ~ 7

Author(s):

Takeshi Makabe ◽

Eri Arai ◽

Takuro Hirano ◽

Nanako Ito ◽

Yukihiro Fukamachi ◽

...

Keyword(s):

Dna Methylation ◽

Endometrial Cancer ◽

Early Onset ◽

Late Onset ◽

Methylation Profile ◽

Cancer Tissue ◽

Cpg Sites ◽

Genome Wide ◽

Dna Methylation Profile ◽

Endometrioid Endometrial Cancer

Abstract The present study was performed to clarify the significance of DNA methylation alterations during endometrial carcinogenesis. Genome-wide DNA methylation analysis and targeted sequencing of tumor-related genes were performed using the Infinium MethylationEPIC BeadChip and the Ion AmpliSeq Cancer Hotspot Panel v2, respectively, for 31 samples of normal control endometrial tissue from patients without endometrial cancer and 81 samples of endometrial cancer tissue. Principal component analysis revealed that tumor samples had a DNA methylation profile distinct from that of control samples. Gene Ontology enrichment analysis revealed significant differences of DNA methylation at 1034 CpG sites between early-onset endometrioid endometrial cancer (EE) tissue (patients aged ≤40 years) and late-onset endometrioid endometrial cancer (LE) tissue, which were accumulated among ‘transcriptional factors’. Mutations of the CTNNB1 gene or DNA methylation alterations of genes participating in Wnt signaling were frequent in EEs, whereas genetic and epigenetic alterations of fibroblast growth factor signaling genes were observed in LEs. Unsupervised hierarchical clustering grouped EE samples in Cluster EA (n = 22) and samples in Cluster EB (n = 12). Clinicopathologically less aggressive tumors tended to be accumulated in Cluster EB, and DNA methylation levels of 18 genes including HOXA9, HOXD10 and SOX11 were associated with differences in such aggressiveness between the two clusters. We identified 11 marker CpG sites that discriminated EB samples from EA samples with 100% sensitivity and specificity. These data indicate that genetically and epigenetically different pathways may participate in the development of EEs and LEs, and that DNA methylation profiling may help predict tumors that are less aggressive and amenable to fertility preservation treatment.

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Testing cell-type-specific mediation effects in genome-wide epigenetic studies

Briefings in Bioinformatics ◽

10.1093/bib/bbaa131 ◽

2020 ◽

Cited By ~ 1

Author(s):

Xiangyu Luo ◽

Joel Schwartz ◽

Andrea Baccarelli ◽

Zhonghua Liu

Keyword(s):

Dna Methylation ◽

Mediation Analysis ◽

Methylation Data ◽

Cell Type ◽

Multiple Testing Procedure ◽

Mediation Effects ◽

Cpg Sites ◽

Genome Wide ◽

A Cell ◽

Cell Type Specific

Abstract Epigenome-wide mediation analysis aims to identify DNA methylation CpG sites that mediate the causal effects of genetic/environmental exposures on health outcomes. However, DNA methylations in the peripheral blood tissues are usually measured at the bulk level based on a heterogeneous population of white blood cells. Using the bulk level DNA methylation data in mediation analysis might cause confounding bias and reduce study power. Therefore, it is crucial to get fine-grained results by detecting mediation CpG sites in a cell-type-specific way. However, there is a lack of methods and software to achieve this goal. We propose a novel method (Mediation In a Cell-type-Specific fashion, MICS) to identify cell-type-specific mediation effects in genome-wide epigenetic studies using only the bulk-level DNA methylation data. MICS follows the standard mediation analysis paradigm and consists of three key steps. In step1, we assess the exposure-mediator association for each cell type; in step 2, we assess the mediator-outcome association for each cell type; in step 3, we combine the cell-type-specific exposure-mediator and mediator-outcome associations using a multiple testing procedure named MultiMed [Sampson JN, Boca SM, Moore SC, et al. FWER and FDR control when testing multiple mediators. Bioinformatics 2018;34:2418–24] to identify significant CpGs with cell-type-specific mediation effects. We conduct simulation studies to demonstrate that our method has correct FDR control. We also apply the MICS procedure to the Normative Aging Study and identify nine DNA methylation CpG sites in the lymphocytes that might mediate the effect of cigarette smoking on the lung function.

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Genome‐wide DNA methylation patterns associated with sleep and mental health in children: a population‐based study

Journal of Child Psychology and Psychiatry ◽

10.1111/jcpp.13252 ◽

2020 ◽

Vol 61 (10) ◽

pp. 1061-1069

Author(s):

Maria Elisabeth Koopman‐Verhoeff ◽

Rosa H. Mulder ◽

Jared M. Saletin ◽

Irwin Reiss ◽

Gijsbertus T.J. Horst ◽

...

Keyword(s):

Mental Health ◽

Dna Methylation ◽

Population Based ◽

Population Based Study ◽

Genome Wide ◽

Methylation Patterns

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PSVIII-39 Genome-wide DNA methylation alteration in prenatally stressed Brahman heifer calves with the advancement of age

Journal of Animal Science ◽

10.1093/jas/skz258.537 ◽

2019 ◽

Vol 97 (Supplement_3) ◽

pp. 263-264

Author(s):

Kubra Z Cilkiz ◽

Emilie C Baker ◽

Penny K Riggs ◽

Ronald D Randel ◽

David G Riley ◽

...

Keyword(s):

Dna Methylation ◽

Regulatory Network ◽

Transcriptional Regulatory Network ◽

Embryonic Stem ◽

Control Group ◽

Promoter Regions ◽

Cpg Sites ◽

Transcriptional Regulatory ◽

Canonical Pathways ◽

Prenatally Stressed

Abstract This study investigated whether DNA methylation patterns changed over the first five yr of life within prenatally stressed (PNS) heifer calves compared to change within a Control group. Prenatal stress was induced by the transportation of pregnant Brahman cows for 2-hr periods at 60±5, 80± 5, 100±5, 120±5, and140±5d of gestation. White blood cells were sampled from the same 6 PNS heifer calves and 8 Control heifer calves at 28 d and 5 yr of age. The DNA methylation data were generated through Reduced Representation Bisulfite Sequencing. Based on results of mapping and bioinformatics analyses, 73,758 hypermethylated and 73,367 hypomethylated CpG sites, 375 hypermethylated and 377 hypomethylated CHG sites, 735 hypermethylated and 842 hypomethylated CHH (C = cytosine; G = guanine; H = either adenine, thymine, or cytosine) sites were obtained from 28-d-old PNS calves compared to when they had matured into 5-yr-old PNS cows (P ≤ 0.05). The 28-d-old Control heifer calves contained 53,005 hypermethylated and 57,103 hypomethylated CpG sites, 200 hypermethylated and 202 hypomethylated CHG sites, 439 hypermethylated and 535 hypomethylated CHH sites compared to when they matured into 5-yr-old Control cows (P ≤ 0.05). As DNA methylation of gene promoter regions is associated with reduced transcription activity, strongly hypermethylated and hypomethylated CpG sites located in promoter regions underwent Ingenuity Pathway Analysis. The top canonical pathways altered by strongly hypermethylated and hypomethylated CpG sites between 28-d-old and 5-yr-old PNS cows were 4-1BB Signaling in T Lymphocytes (P = 0.00169) and Transcriptional Regulatory Network in Embryonic Stem Cells (P = 0.000744). Mineralocorticoid Biosynthesis (P = 0.00901) and Transcriptional Regulatory Network in Embryonic Stem Cells (P = 0.000804) were the other top canonical pathways altered between 28-d-old and 5-yr-old Control cows. PNS calves appeared to develop an altered epigenome compared to Control group calves during the first five yr from birth.

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