Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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    Influence of nutrients involved in one-carbon metabolism on DNA methylation in adults-a systematic review and meta-analysis
    Amenyah, Sophia D. ; Hughes, Catherine F. ; Ward, Mary ; Rosborough, Samuel ; Deane, Jennifer ; Thursby, Sara Jayne ; Walsh, Colum P. ; Kok, Dieuwertje E. ; Strain, J.J. ; McNulty, Helene ; Lees-Murdock, Diane J. - \ 2020
    Nutrition Reviews 78 (2020)8. - ISSN 0029-6643 - p. 647 - 666.
    B vitamins - DNA methylation - meta-analysis - systematic review

    CONTEXT: Aberrant DNA methylation is linked to various diseases. The supply of methyl groups for methylation reactions is mediated by S-adenosylmethionine, which depends on the availability of folate and related B vitamins. OBJECTIVES: To investigate the influence of key nutrients involved in 1-carbon metabolism on DNA methylation in adults. DATA SOURCES: Systematic literature searches were conducted in the Cochrane Library, Medline, Embase, Cumulative Index to Nursing and Allied Health Literature Plus, Scopus, and Web of Science databases. Studies that met the inclusion criteria and were published in English were included. DATA EXTRACTION: The first author, study design, sample size, population characteristics, type and duration of intervention, tissue type or cells analyzed, molecular techniques, and DNA methylation outcomes. DATA SYNTHESIS: A meta-analysis of randomized, controlled trials (RCTs) was conducted to investigate the effect of 1-carbon metabolism nutrients on global DNA methylation. Functional analysis and visualization were performed using BioVenn software. RESULTS: From a total of 2620 papers screened by title, 53 studies met the inclusion criteria. Qualitative analysis indicated significant associations between 1-carbon metabolism nutrients and DNA methylation. In meta-analysis of RCTs stratified by method of laboratory analysis, supplementation with folic acid alone or in combination with vitamin B12 significantly increased global DNA methylation in studies using liquid chromatography-mass spectrometry, which had markedly lower heterogeneity (n = 3; Z = 3.31; P = 0.0009; I2 = 0%) in comparison to other methods. Functional analysis highlighted a subset of 12 differentially methylated regions that were significantly related to folate and vitamin B12 biomarkers. CONCLUSION: This study supports significant associations between 1-carbon metabolism nutrients and DNA methylation. However, standardization of DNA methylation techniques is recommended to reduce heterogeneity and facilitate comparison across studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42018091898.

    Genome-wide detection of key genes and epigenetic markers for chicken fatty liver
    Tan, Xiaodong ; Liu, Ranran ; Xing, Siyuan ; Zhang, Yonghong ; Li, Qinghe ; Zheng, Maiqing ; Zhao, Guiping ; Wen, Jie - \ 2020
    International Journal of Molecular Sciences 21 (2020)5. - ISSN 1661-6596
    Chicken - DNA methylation - Epigenetics - Fatty liver - Lipid metabolism - Long noncoding RNA

    Chickens are one of the most important sources of meat worldwide, and the occurrence of fatty liver syndrome (FLS) is closely related to production efficiency. However, the potential mechanism of FLS remains poorly understood. An integrated analysis of data from whole-genome bisulfite sequencing and long noncoding RNA (lncRNA) sequencing was conducted. A total of 1177 differentially expressed genes (DEGs) and 1442 differentially methylated genes (DMGs) were found. There were 72% of 83 lipid-and glucose-related genes upregulated; 81% of 150 immune-related genes were downregulated in fatty livers. Part of those genes was within differentially methylated regions (DMRs). Besides, sixty-seven lncRNAs were identified differentially expressed and divided into 13 clusters based on their expression pattern. Some lipid-and glucose-related lncRNAs (e.g., LNC_006756, LNC_012355, and LNC_005024) and immune-related lncRNAs (e.g., LNC_010111, LNC_010862, and LNC_001272) were found through a co-expression network and functional annotation. From the expression and epigenetic profiles, 23 target genes (e.g., HAO1, ABCD3, and BLMH) were found to be hub genes that were regulated by both methylation and lncRNAs. We have provided comprehensive epigenetic and transcriptomic profiles on FLS in chicken, and the identification of key genes and epigenetic markers will expand our understanding of the molecular mechanism of chicken FLS.

    Epigenetic Approaches in Non-Model Plants
    Boquete, Teresa M. ; Wagemaker, Niels C.A.M. ; Vergeer, Philippine ; Mounger, Jeannie ; Richards, Christina L. - \ 2020
    In: Plant Epigenetics and Epigenomics Methods in molecular biology 2093 (2020). - ISSN 1064-3745New York : Humana Press (Methods in molecular biology (Clifton, N.J.) ) - ISBN 9781071601785 - p. 203 - 215.
    Bisulfite treatment - DNA methylation - epiGBS - Epigenetics - Multiplexing - Next-generation sequencing - Reduced representation sequencing - Restriction enzymes

    Reduced representation bisulfite sequencing is an emerging methodology for evolutionary and ecological genomics and epigenomics research because it provides a cost-effective, high-resolution tool for exploration and comparative analysis of DNA methylation and genetic variation. Here we describe how digestion of genomic plant DNA with restriction enzymes, subsequent bisulfite conversion of unmethylated cytosines, and final DNA sequencing allow for the examination of genome-wide genetic and epigenetic variation in plants without the need for a reference genome. We explain how the use of several combinations of barcoded adapters for the creation of highly multiplexed libraries allows the inclusion of up to 144 different samples/individuals in only one sequencing lane.

    Altered hippocampal epigenetic regulation underlying reduced cognitive development in response to early life environmental insults
    Schachtschneider, Kyle M. ; Welge, Michael E. ; Auvil, Loretta S. ; Chaki, Sulalita ; Rund, Laurie A. ; Madsen, Ole ; Elmore, Monica R.P. ; Johnson, Rodney W. ; Groenen, Martien A.M. ; Schook, Lawrence B. - \ 2020
    Genes 11 (2020)2. - ISSN 2073-4425
    Cognitive development - DNA methylation - Hippocampus - Machine learning - Porcine biomedical models - RNA-seq

    The hippocampus is involved in learning and memory and undergoes significant growth and maturation during the neonatal period. Environmental insults during this developmental timeframe can have lasting effects on brain structure and function. This study assessed hippocampal DNA methylation and gene transcription from two independent studies reporting reduced cognitive development stemming from early life environmental insults (iron deficiency and porcine reproductive and respiratory syndrome virus (PRRSv) infection) using porcine biomedical models. In total, 420 differentially expressed genes (DEGs) were identified between the reduced cognition and control groups, including genes involved in neurodevelopment and function. Gene ontology (GO) terms enriched for DEGs were associated with immune responses, angiogenesis, and cellular development. In addition, 116 differentially methylated regions (DMRs) were identified, which overlapped 125 genes. While no GO terms were enriched for genes overlapping DMRs, many of these genes are known to be involved in neurodevelopment and function, angiogenesis, and immunity. The observed altered methylation and expression of genes involved in neurological function suggest reduced cognition in response to early life environmental insults is due to altered cholinergic signaling and calcium regulation. Finally, two DMRs overlapped with two DEGs, VWF and LRRC32, which are associated with blood brain barrier permeability and regulatory T-cell activation, respectively. These results support the role of altered hippocampal DNA methylation and gene expression in early life environmentally-induced reductions in cognitive development across independent studies.

    Mutation dynamics of CpG dinucleotides during a recent event of vertebrate diversification
    Pértille, Fábio ; Silva, Vinicius da; Johansson, Anna M. ; Lindström, Tom ; Wright, Dominic ; Luiz da Costa Coutinho, Heitor da; Jensen, Per ; Guerrero-Bosagna, Carlos - \ 2019
    Linköping University
    PRJEB29249 - ERP111539 - genetic variation - DNA methylation - CpG - single nucleotide polymorphisms - copy number variations - germ line - Gallus gallus
    Seasonal Variation in Genome-Wide DNA Methylation Patterns and the Onset of Seasonal Timing of Reproduction in Great Tits
    Viitaniemi, Heidi M. ; Verhagen, Irene ; Visser, Marcel E. ; Honkela, Antti ; Oers, Kees van; Husby, Arild - \ 2019
    Genome Biology and Evolution 11 (2019)3. - ISSN 1759-6653 - p. 970 - 983.
    DNA methylation - epigenetics - laying date. - Parus major - RRBS - timing of reproduction

    In seasonal environments, timing of reproduction is a traitwith important fitness consequences, butwe know little about the molecular mechanisms that underlie the variation in this trait. Recently, several studies put forward DNA methylation as a mechanism regulating seasonal timing of reproduction in both plants and animals. To understand the involvement of DNA methylation in seasonal timing of reproduction, it is necessary to examine within-individual temporal changes in DNA methylation, but such studies are very rare. Here, we use a temporal sampling approach to examine changes in DNA methylation throughout the breeding season in female great tits (Parus major) that were artificially selected for early timing of breeding. These females were housed in climate-controlled aviaries and subjected to two contrasting temperature treatments. Reduced representation bisulfite sequencing on red blood cell derived DNA showed genome-wide temporal changes inmore than 40,000 out of the 522,643 CpG sites examined. Althoughmost of these changeswere relatively small (mean within-individual change of 6%), the sites that showed a temporal and treatment-specific response in DNA methylation are candidate sites of interest for future studies trying to understand the link between DNAmethylation patterns and timing of reproduction.

    Evidence for rapid evolution in a grassland biodiversity experiment
    Moorsel, Sofia J. van; Schmid, Marc W. ; Wagemaker, Niels C.A.M. ; Gurp, Thomas van; Schmid, Bernhard ; Vergeer, Philippine - \ 2019
    Molecular Ecology 28 (2019)17. - ISSN 0962-1083 - p. 4097 - 4117.
    biodiversity - DNA methylation - epigenetic variation - genetic divergence - herbaceous plant species - selection

    In long-term grassland experiments, positive biodiversity effects on plant productivity commonly increase with time. Subsequent glasshouse experiments showed that these strengthened positive biodiversity effects persist not only in the local environment but also when plants are transferred into a common environment. Thus, we hypothesized that community diversity had acted as a selective agent, resulting in the emergence of plant monoculture and mixture types with differing genetic composition. To test our hypothesis, we grew offspring from plants that were grown for eleven years in monoculture or mixture environments in a biodiversity experiment (Jena Experiment) under controlled glasshouse conditions in monocultures or two-species mixtures. We used epiGBS, a genotyping-by-sequencing approach combined with bisulphite conversion, to provide integrative genetic and epigenetic (i.e., DNA methylation) data. We observed significant divergence in genetic and DNA methylation data according to selection history in three out of five perennial grassland species, namely Galium mollugo, Prunella vulgaris and Veronica chamaedrys, with DNA methylation differences mostly reflecting the genetic differences. In addition, current diversity levels in the glasshouse had weak effects on epigenetic variation. However, given the limited genome coverage of the reference-free bisulphite method epiGBS, it remains unclear how much of the differences in DNA methylation was independent of underlying genetic differences. Our results thus suggest that selection of genetic variants, and possibly epigenetic variants, caused the rapid emergence of monoculture and mixture types within plant species in the Jena Experiment.

    Contribution of methylation regulation of MpDREB2A promoter to drought resistance of Mauls prunifolia
    Li, Xuewei ; Xie, Yinpeng ; Lu, Liyuan ; Yan, Mingjia ; Fang, Nan ; Xu, Jidi ; Wang, Liping ; Yan, Yan ; Zhao, Tao ; Nocker, Steve van; Ma, Fengwang ; Liang, Dong ; Guan, Qingmei - \ 2019
    Plant and Soil 441 (2019)1-2. - ISSN 0032-079X - p. 15 - 32.
    ChIP-seq - DNA methylation - DREB2A - Drought resistance - Gene expression - Malus

    Background and aims: Malus prunifolia (Chinese name: Fu Ping Qiu Zi), a wild relative of cultivated apple (Malus x domestica Borkh), is extremely resistant to drought compared with domesticated cultivars, such as ‘Golden Delicious’. However, the molecular mechanisms underlying drought resistance of M. prunifolia have not been characterized. This study investigates a new regulatory mechanism to improve apple drought resistance. Methods: M. prunifolia and ‘Golden Delicious’ were each grafted on M. hupehensis for gene expression analysis. The methylation level of the DREB2A promoter was determined by bisulfite sequencing and ChIP-qPCR. Chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify target genes of MpDREB2A in apple. Results: The exposure to drought stress stimulated the expression level of DREB2A gene more than 100-fold in M. prunifolia, but only 16-fold in ‘Golden Delicious’. This difference in gene expression could not be explained in terms of difference in leaf relative water content. Correspondingly, the methylation level of M. prunifolia DREB2A (MpDREB2A) promoter region was significantly reduced. Additionally, MpDREB2A conferred enhanced drought resistance when ectopically expressed in Arabidopsis. Over 2800 potential downstream target genes of MpDREB2A were identified by ChIP-seq and these downstream genes have diverse potential functions related to stress resistance. Conclusions: Methylation regulation in promoter of MpDREB2A may contribute to the drought resistance of M. prunifolia.

    Validating the demethylating effects of 5-aza-20-deoxycytidine in insects requires a whole-genome approach (A reply to Ellers et al.)
    Cook, Nicola ; Parker, Darren J. ; Tauber, Eran ; Pannebakker, Bart A. ; Shuker, David M. - \ 2019
    American Naturalist 194 (2019)3. - ISSN 0003-0147 - p. 432 - 438.
    5-aza-2-deoxycytidine - DNA methylation - Nasonia vitripennis - Sex ratio

    We previously demonstrated that treatment with the de-methylating agent 5-aza-20-deoxycytidine (5-aza-dC) alters the offspring sex ratios produced by females of the parasitoid wasp Nasonia vitripennis. Females allocate offspring sex ratio in line with local mate competition theory, producing more or less female-biased sex ratios as the number of other females laying eggs on a patch varies, thereby reducing competition among their sons for mates. Interestingly, treatment with 5-aza-dC did not ablate the facultative sex allocation re-sponse. Instead, sex ratios became less female biased, a shift in the direction of the optimum sex ratio for paternally inherited alleles ac-cording to genomic conflict theory. This was the first (albeit indirect) experimental evidence for genomic conflict over sex allocation. In their comment, Ellers and colleagues assayed the effects of 5-aza-dC on DNA methylation in 10 Nasonia genes, finding no evidence of demeth-ylation in these 10 genes, from which they conclude that 5-aza-dC has no demethylating capability in N. vitripennis. Quantifying the efficacy of 5-aza-dC in terms of demethylation is indeed crucial to in-depth interpretation of studies using 5-aza-dC to link phenotypes to epigenetic regulation. Here we outline the mode of action of 5-aza-dC and demonstrate that determining the efficacy of 5-aza-dC in insect systems requires a whole-genome approach.

    Mutation dynamics of CpG dinucleotides during a recent event of vertebrate diversification
    Pértille, Fábio ; Silva, Vinicius H. Da; Johansson, Anna M. ; Lindström, Tom ; Wright, Dominic ; Coutinho, Luiz L. ; Jensen, Per ; Guerrero-Bosagna, Carlos - \ 2019
    Epigenetics 14 (2019)7. - ISSN 1559-2294 - p. 685 - 707.
    copy number variations - CpG - DNA methylation - Gallus gallus - genetic variation - germ line - single nucleotide polymorphisms

    DNA methylation in CpGs dinucleotides is associated with high mutability and disappearance of CpG sites during evolution. Although the high mutability of CpGs is thought to be relevant for vertebrate evolution, very little is known on the role of CpG-related mutations in the genomic diversification of vertebrates. Our study analysed genetic differences in chickens, between Red Junglefowl (RJF; the living closest relative to the ancestor of domesticated chickens) and domesticated breeds, to identify genomic dynamics that have occurred during the process of their domestication, focusing particularly on CpG-related mutations. Single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) between RJF and these domesticated breeds were assessed in a reduced fraction of their genome. Additionally, DNA methylation in the same fraction of the genome was measured in the sperm of RJF individuals to identify possible correlations with the mutations found between RJF and the domesticated breeds. Our study shows that although the vast majority of CpG-related mutations found relate to CNVs, CpGs disproportionally associate to SNPs in comparison to CNVs, where they are indeed substantially under-represented. Moreover, CpGs seem to be hotspots of mutations related to speciation. We suggest that, on the one hand, CpG-related mutations in CNV regions would promote genomic ‘flexibility’ in evolution, i.e., the ability of the genome to expand its functional possibilities; on the other hand, CpG-related mutations in SNPs would relate to genomic ‘specificity’ in evolution, thus, representing mutations that would associate with phenotypic traits relevant for speciation.

    Selective Survival of Embryos Can Explain DNA Methylation Signatures of Adverse Prenatal Environments
    Tobi, Elmar W. ; Heuvel, Joost van den; Zwaan, Bas J. ; Lumey, L.H. ; Heijmans, Bastiaan T. ; Uller, Tobias - \ 2018
    Cell Reports 25 (2018)10. - ISSN 2211-1247 - p. 2660 - 2667.e4.
    developmental origins - DNA methylation - plasticity - selection

    An adverse intrauterine environment is associated with long-term physiological changes in offspring. These are believed to be mediated by epigenomic marks, including DNA methylation (DNAm). Changes in DNAm are often interpreted as damage or plastic responses of the embryo. Here, we propose that stochastic DNAm variation, generated during remodeling of the epigenome after fertilization, contributes to DNAm signatures of prenatal adversity through differential survival of embryos. Using a mathematical model of re-methylation in the early embryo, we demonstrate that selection, but not plasticity, will generate a characteristic reduction in DNAm variance at loci that contribute to survival. Such a reduction in DNAm variance was apparent in a human cohort prenatally exposed to the Dutch famine, illustrating that it is possible to detect a signature of selection on epigenomic variation. Selection should be considered as a possible mechanism linking prenatal adversity to subsequent health and may have implications when evaluating interventions.

    Folate and epigenetics : Why we should not forget bacterial biosynthesis
    Kok, Dieuwertje E. ; Steegenga, Wilma T. ; McKay, Jill A. - \ 2018
    Epigenomics 10 (2018)9. - ISSN 1750-1911 - p. 1147 - 1150.
    biosynthesis - DNA methylation - epigenetics - folate - intestinal bacteria - microbiota - one-carbon metabolism
    Data from: Increased transgenerational epigenetic variation, but not predictable epigenetic variants, after environmental exposure in two apomictic dandelion lineages
    Preite, Veronica ; Oplaat, Carla ; Biere, Arjen ; Kirschner, Jan ; Putten, W.H. van der; Verhoeven, Koen J.F. - \ 2018
    NIOO-KNAW
    DNA methylation - stress memory - drought - salicylic acid - Taraxacum officinale
    DNA methylation is one of the mechanisms underlying epigenetic modifications. DNA methylations can be environmentally induced and such induced modifications can at times be transmitted to successive generations. However, it remains speculative how common such environmentally induced transgenerational DNA methylation changes are and if they persist for more than one offspring generation. We exposed multiple accessions of two different apomictic dandelion lineages of the Taraxacum officinale group (Taraxacum alatum and T. hemicyclum) to drought and salicylic acid (SA) treatment. Using methylation-sensitive amplified fragment length polymorphism markers (MS-AFLPs) we screened anonymous methylation changes at CCGG restriction sites throughout the genome after stress treatments and assessed the heritability of induced changes for two subsequent unexposed offspring generations. Irrespective of the initial stress treatment, a clear buildup of heritable DNA methylation variation was observed across three generations, indicating a considerable background rate of heritable epimutations. Less evidence was detected for environmental effects. Drought stress showed some evidence for accession-specific methylation changes, but only in the exposed generation and not in their offspring. By contrast, SA treatment caused an increased rate of methylation change in offspring of treated plants. These changes were seemingly undirected resulting in increased transgenerational epigenetic variation between offspring individuals, but not in predictable epigenetic variants. While the functional consequences of these MS-AFLP-detected DNA methylation changes remain to be demonstrated, our study shows that (1) stress-induced transgenerational DNA methylation modification in dandelions is genotype and context-specific; and (2) inherited environmental DNA methylation effects are mostly undirected and not targeted to specific loci.
    Increased transgenerational epigenetic variation, but not predictable epigenetic variants, after environmental exposure in two apomictic dandelion lineages
    Preite, Veronica ; Oplaat, Carla ; Biere, Arjen ; Kirschner, Jan ; Putten, Wim H. van der; Verhoeven, Koen J.F. - \ 2018
    Ecology and Evolution 8 (2018)5. - ISSN 2045-7758 - p. 3047 - 3059.
    DNA methylation - drought - Europe - salicylic acid - stress memory - Taraxacum officinale
    DNA methylation is one of the mechanisms underlying epigenetic modifications. DNA methylations can be environmentally induced and such induced modifications can at times be transmitted to successive generations. However, it remains speculative how common such environmentally induced transgenerational DNA methylation changes are and if they persist for more than one offspring generation. We exposed multiple accessions of two different apomictic dandelion lineages of the Taraxacum officinale group (Taraxacum alatum and T. hemicyclum) to drought and salicylic acid (SA) treatment. Using methylation-sensitive amplified fragment length polymorphism markers (MS-AFLPs) we screened anonymous methylation changes at CCGG restriction sites throughout the genome after stress treatments and assessed the heritability of induced changes for two subsequent unexposed offspring generations. Irrespective of the initial stress treatment, a clear buildup of heritable DNA methylation variation was observed across three generations, indicating a considerable background rate of heritable epimutations. Less evidence was detected for environmental effects. Drought stress showed some evidence for accession-specific methylation changes, but only in the exposed generation and not in their offspring. By contrast, SA treatment caused an increased rate of methylation change in offspring of treated plants. These changes were seemingly undirected resulting in increased transgenerational epigenetic variation between offspring individuals, but not in predictable epigenetic variants. While the functional consequences of these MS-AFLP-detected DNA methylation changes remain to be demonstrated, our study shows that (1) stress-induced transgenerational DNA methylation modification in dandelions is genotype and context-specific; and (2) inherited environmental DNA methylation effects are mostly undirected and not targeted to specific loci.
    Plasticity of lifelong calorie-restricted C57BL/6J mice in adapting to a medium-fat diet intervention at old age
    Rusli, Fenni ; Boekschoten, Mark V. ; Borelli, Vincenzo ; Sun, Chen ; Lute, Carolien ; Menke, Aswin L. ; Heuvel, Joost van den; Salvioli, Stefano ; Franceschi, Claudio ; Müller, Michael ; Steegenga, Wilma T. - \ 2018
    Aging Cell 17 (2018)2. - ISSN 1474-9718
    NAFLD - Aging - DNA methylation - Glycomics - Liver - Long-term CR - Transcriptomics
    Calorie restriction (CR) is a dietary regimen that supports healthy aging. In this study, we investigated the systemic and liver-specific responses caused by a diet switch to a medium-fat (MF) diet in 24-month-old lifelong, CR-exposed mice. This study aimed to increase the knowledge base on dietary alterations of gerontological relevance. Nine-week-old C57BL/6J mice were exposed either to a control, CR, or MF diet. At the age of 24 months, a subset of mice of the CR group was transferred to ad libitumMF feeding (CR-MF). The mice were sacrificed at the age of 28 months, and then, biochemical and molecular analyses were performed. Our results showed that, despite the long-term exposure to the CR regimen, mice in the CR-MF group displayed hyperphagia, rapid weight gain, and hepatic steatosis. However, no hepatic fibrosis/injury or alteration in CR-improved survival was observed in the diet switch group. The liver transcriptomic profile of CR-MF mice largely shifted to a profile similar to the MF-fed animals but leaving ~22% of the 1,578 differentially regulated genes between the CR and MF diet groups comparable with the expression of the lifelong CR group. Therefore, although the diet switch was performed at an old age, the CR-MF-exposed mice showed plasticity in coping with the challenge of a MF diet without developing severe liver pathologies.
    Persistent organic pollutants alter DNA methylation during human adipocyte differentiation
    Dungen, Myrthe W. van den; Murk, Albertinka J. ; Gils-Kok, Dieuwertje van; Steegenga, Wilma T. - \ 2017
    Toxicology in Vitro 40 (2017). - ISSN 0887-2333 - p. 79 - 87.
    Adipocytes - DNA methylation - Gene expression - Human mesenchymal stem cells - Infinium 450K BeadChip - Persistent organic pollutants (POPs)

    Ubiquitous persistent organic pollutants (POPs) can accumulate in humans where they might influence differentiation of adipocytes. The aim of this study was to investigate whether DNA methylation is one of the underlying mechanisms by which POPs affect adipocyte differentiation, and to what extent DNA methylation can be related to gene transcription. Adipocyte differentiation was induced in two human cell models with continuous exposure to different POPs throughout differentiation. From the seven tested POPs, perfluorooctanesulfonic acid (PFOS) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) decreased lipid accumulation, while tributyltin (TBT) increased lipid accumulation. In human mesenchymal stem cells (hMSCs), TCDD and TBT induced opposite gene expression profiles, whereas after PFOS exposure gene expression remained relatively stable. Genome-wide DNA methylation analysis showed that all three POPs affected DNA methylation patterns in adipogenic and other genes, possibly related to the phenotypic outcome, but without concomitant gene expression changes. Differential methylation was predominantly detected in intergenic regions, where the biological relevance of alterations in DNA methylation is unclear. This study demonstrates that POPs, at environmentally relevant levels, are able to induce differential DNA methylation in human differentiating adipocytes.

    Genome-wide epigenomic profiling for biomarker discovery
    Dirks, René A.M. ; Stunnenberg, Hendrik G. ; Marks, Hendrik - \ 2016
    Clinical Epigenetics 8 (2016)1. - ISSN 1868-7075
    ATAC-Seq - Automation - Biomarker discovery - DNA methylation - Genome-wide epigenetic profiling - Miniaturization - Precision medicine - Single cell - Stratification - WGBS

    A myriad of diseases is caused or characterized by alteration of epigenetic patterns, including changes in DNA methylation, post-translational histone modifications, or chromatin structure. These changes of the epigenome represent a highly interesting layer of information for disease stratification and for personalized medicine. Traditionally, epigenomic profiling required large amounts of cells, which are rarely available with clinical samples. Also, the cellular heterogeneity complicates analysis when profiling clinical samples for unbiased genome-wide biomarker discovery. Recent years saw great progress in miniaturization of genome-wide epigenomic profiling, enabling large-scale epigenetic biomarker screens for disease diagnosis, prognosis, and stratification on patient-derived samples. All main genome-wide profiling technologies have now been scaled down and/or are compatible with single-cell readout, including: (i) Bisulfite sequencing to determine DNA methylation at base-pair resolution, (ii) ChIP-Seq to identify protein binding sites on the genome, (iii) DNaseI-Seq/ATAC-Seq to profile open chromatin, and (iv) 4C-Seq and HiC-Seq to determine the spatial organization of chromosomes. In this review we provide an overview of current genome-wide epigenomic profiling technologies and main technological advances that allowed miniaturization of these assays down to single-cell level. For each of these technologies we evaluate their application for future biomarker discovery. We will focus on (i) compatibility of these technologies with methods used for clinical sample preservation, including methods used by biobanks that store large numbers of patient samples, and (ii) automation of these technologies for robust sample preparation and increased throughput.

    Evidence from pyrosequencing indicates that natural variation in animal personality is associated with DRD4 DNA methylation
    Verhulst, Eveline C. ; Mateman, A.C. ; Zwier, Mathijs V. ; Caro, Samuel P. ; Verhoeven, Koen J.F. ; Oers, Kees Van - \ 2016
    Molecular Ecology 25 (2016)8. - ISSN 0962-1083 - p. 1801 - 1811.
    behaviour - birds - DNA methylation - epigenetics - personality

    Personality traits are heritable and respond to natural selection, but are at the same time influenced by the ontogenetic environment. Epigenetic effects, such as DNA methylation, have been proposed as a key mechanism to control personality variation. However, to date little is known about the contribution of epigenetic effects to natural variation in behaviour. Here, we show that great tit (Parus major) lines artificially selected for divergent exploratory behaviour for four generations differ in their DNA methylation levels at the dopamine receptor D4 (DRD4) gene. This D4 receptor is statistically associated with personality traits in both humans and nonhuman animals, including the great tit. Previous work in this songbird failed to detect functional genetic polymorphisms within DRD4 that could account for the gene-trait association. However, our observation supports the idea that DRD4 is functionally involved in exploratory behaviour but that its effects are mediated by DNA methylation. While the exact mechanism underlying the transgenerational consistency of DRD4 methylation remains to be elucidated, this study shows that epigenetic mechanisms are involved in shaping natural variation in personality traits. We outline how this first finding provides a basis for investigating the epigenetic contribution to personality traits in natural systems and its subsequent role for understanding the ecology and evolution of behavioural consistency.

    Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes
    Jetten, M.J.A. ; Blanco Garcia, Ainhoa ; Coonen, M.L.J. ; Claessen, Sandra ; Herwijnen, M.H.M. van; Lommen, Arjen ; Delft, J.H.M. van; Peijnenburg, A.A.C.M. ; Kleinjans, J.C.S. - \ 2016
    Archives of Toxicology (2016). - ISSN 0340-5761 - p. 1103 - 1115.
    Aflatoxin b1 - Benzo(a)pyrene - DNA methylation - Gene expression - Interindividual variation - Primary human hepatocytes

    Acetaminophen (APAP) is a readily available over-the-counter drug and is one of the most commonly used analgesics/antipyretics worldwide. Large interindividual variation in susceptibility toward APAP-induced liver failure has been reported. However, the exact underlying factors causing this variability in susceptibility are still largely unknown. The aim of this study was to better understand this variability in response to APAP by evaluating interindividual differences in gene expression changes and APAP metabolite formation in primary human hepatocytes (PHH) from several donors (n = 5) exposed in vitro to a non-toxic to toxic APAP dose range. To evaluate interindividual variation, gene expression data/levels of metabolites were plotted against APAP dose/donor. The correlation in APAP dose response between donors was calculated by comparing data points from one donor to the data points of all other donors using a Pearson-based correlation analysis. From that, a correlation score/donor for each gene/metabolite was defined, representing the similarity of the omics response to APAP in PHH of a particular donor to all other donors. The top 1 % highest variable genes were selected for further evaluation using gene set overrepresentation analysis. The biological processes in which the genes with high interindividual variation in expression were involved include liver regeneration, inflammatory responses, mitochondrial stress responses, hepatocarcinogenesis, cell cycle, and drug efficacy. Additionally, the interindividual variation in the expression of these genes could be associated with the variability in expression levels of hydroxyl/methoxy-APAP and C8H13O5N-APAP-glucuronide. The before-mentioned metabolites or their derivatives have also been reported in blood of humans exposed to therapeutic APAP doses. Possibly these findings can contribute to elucidating the causative factors of interindividual susceptibility toward APAP.

    Data from: The epigenetic footprint of poleward range-expanding plants in apomictic dandelions
    Preite, V. ; Snoek, Basten ; Oplaat, C. ; Biere, A. ; Putten, Wim van der; Verhoeven, K.J.F. - \ 2015
    Wageningen University & Research
    range expansion - DNA methylation - Taraxacum officinale - natural populations - MS-AFLP - epigenetic inheritance - apomictic dandelions
    Epigenetic modifications, such as DNA methylation variation, can generate heritable phenotypic variation independent of the underlying genetic code. However, epigenetic variation in natural plant populations is poorly documented and little understood. Here, we test whether northward range expansion of obligate apomicts of the common dandelion (Taraxacum officinale) is associated with DNA methylation variation. We characterized and compared patterns of genetic and DNA methylation variation in greenhouse-reared offspring of T. officinale that were collected along a latitudinal transect of northward range expansion in Europe. Genetic AFLP and epigenetic MS-AFLP markers revealed high levels of local diversity and modest but significant heritable differentiation between sampling locations and between the southern, central and northern regions of the transect. Patterns of genetic and epigenetic variation were significantly correlated, reflecting the genetic control over epigenetic variation and/or the accumulation of lineage-specific spontaneous epimutations, which may be selectively neutral. In addition, we identified a small component of DNA methylation differentiation along the transect that is independent of genetic variation. This epigenetic differentiation might reflect environment-specific induction or, in case the DNA methylation variation affects relevant traits and fitness, selection of heritable DNA methylation variants. Such generated epigenetic variants might contribute to the adaptive capacity of individual asexual lineages under changing environments. Our results highlight the potential of heritable DNA methylation variation to contribute to population differentiation along ecological gradients. Further studies are needed using higher resolution methods to understand the functional significance of such natural occurring epigenetic differentiation.
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