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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    Early-onset preeclampsia, plasma microRNAs, and endothelial cell function
    Lip, Simone V. ; Boekschoten, Mark V. ; Hooiveld, Guido J. ; Pampus, Mariëlle G. van; Scherjon, Sicco A. ; Plösch, Torsten ; Faas, Marijke M. - \ 2020
    American Journal of Obstetrics and Gynecology 222 (2020)5. - ISSN 0002-9378 - p. E1 - E497.
    biomarker - endothelial cells - endothelial dysfunction - epigenetics - HUVEC - microarrays - microRNAs - miR-1972 - miR-4793-3p - miR-574-5p - preeclampsia - proliferation - systemic inflammation - transfection - tube formation - wound healing

    Background: Preeclampsia is a hypertensive pregnancy disorder in which generalized systemic inflammation and maternal endothelial dysfunction are involved in the pathophysiology. MiRNAs are small noncoding RNAs responsible for post-transcriptional regulation of gene expression and involved in many physiological processes. They mainly downregulate translation of their target genes. Objective: We aimed to compare the plasma miRNA concentrations in preeclampsia, healthy pregnant women, and nonpregnant women. Furthermore, we aimed to evaluate the effect of 3 highly increased plasma miRNAs in preeclampsia on endothelial cell function in vitro. Study Design: We compared 3391 (precursor) miRNA concentrations in plasma samples from early-onset preeclamptic women, gestational age–matched healthy pregnant women, and nonpregnant women using miRNA 3.1. arrays (Affymetrix) and validated our findings by real-time quantitative polymerase chain reaction. Subsequently, endothelial cells (human umbilical vein endothelial cells) were transfected with microRNA mimics (we choose the 3 miRNAs with the greatest fold change and lowest false-discovery rate in preeclampsia vs healthy pregnancy). After transfection, functional assays were performed to evaluate whether overexpression of the microRNAs in endothelial cells affected endothelial cell function in vitro. Functional assays were the wound-healing assay (which measures cell migration and proliferation), the proliferation assay, and the tube-formation assay (which assesses formation of endothelial cell tubes during the angiogenic process). To determine whether the miRNAs are able to decrease gene expression of certain genes, RNA was isolated from transfected endothelial cells and gene expression (by measuring RNA expression) was evaluated by gene expression microarray (Genechip Human Gene 2.1 ST arrays; Life Technologies). For the microarray, we used pooled samples, but the differently expressed genes in the microarray were validated by real-time quantitative polymerase chain reaction in individual samples. Results: No significant differences (fold change <–1.2 or >1.2 with a false-discovery rate <0.05) were found in miRNA plasma concentrations between healthy pregnant and nonpregnant women. The plasma concentrations of 26 (precursor) miRNAs were different between preeclampsia and healthy pregnancy. The 3 miRNAs that were increased with the greatest fold change and lowest false-discovery rate in preeclampsia vs healthy pregnancy were miR-574-5p, miR-1972, and miR-4793-3p. Transfection of endothelial cells with these miRNAs in showed that miR-574-5p decreased (P<.05) the wound-healing capacity (ie, decreased endothelial cell migration and/or proliferation) and tended (P<.1) to decrease proliferation, miR-1972 decreased tube formation (P<.05), and also tended (P<.1) to decrease proliferation, and miR-4793-3p tended (P<.1) to decrease both the wound-healing capacity and tube formation in vitro. Gene expression analysis of transfected endothelial cells revealed that miR-574-5p tended (P<.1) to decrease the expression of the proliferation marker MKI67. Conclusion: We conclude that in the early-onset preeclampsia group in our study different concentrations of plasma miRNAs are present as compared with healthy pregnancy. Our results suggest that miR-574-5p and miR-1972 decrease the proliferation (probably via decreasing MKI67) and/or migration as well as the tube-formation capacity of endothelial cells. Therefore, these miRNAs may be antiangiogenic factors affecting endothelial cells in preeclampsia.

    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.

    Integrative Proteomic Profiling Reveals PRC2-Dependent Epigenetic Crosstalk Maintains Ground-State Pluripotency
    Mierlo, Guido van; Dirks, René A.M. ; Clerck, Laura De; Brinkman, Arie B. ; Huth, Michelle ; Kloet, Susan L. ; Saksouk, Nehmé ; Kroeze, Leonie I. ; Willems, Sander ; Farlik, Matthias ; Bock, Christoph ; Jansen, Joop H. ; Deforce, Dieter ; Vermeulen, Michiel ; Déjardin, Jérôme ; Dhaenens, Maarten ; Marks, Hendrik - \ 2019
    Cell Stem Cell 24 (2019)1. - ISSN 1934-5909 - p. 123 - 137.e8.
    chromatin profiling - embryonic stem cells - epigenetics - ground-state pluripotency - H3K27me3 - histone modifications

    Marks and colleagues use integrative mass spectrometry to profile post-translational histone modifications and the chromatin-associated proteome in ground-state pluripotency. This reveals H3K27me3 and PRC2 as widespread hallmarks on euchromatin and heterochromatin. They show that ubiquitous chromatin-associated PRC2 protects the epigenome from priming, in particular from gaining DNA methylation.

    Comparison of smoking-related DNA methylation between newborns from prenatal exposure and adults from personal smoking
    Sikdar, Sinjini ; Joehanes, Roby ; Joubert, Bonnie R. ; Xu, Cheng Jian ; Vives-Usano, Marta ; Rezwan, Faisal I. ; Felix, Janine F. ; Ward, James M. ; Guan, Weihua ; Richmond, Rebecca C. ; Brody, Jennifer A. ; Küpers, Leanne K. ; Baïz, Nour ; Håberg, Siri E. ; Smith, Jennifer A. ; Reese, Sarah E. ; Aslibekyan, Stella ; Hoyo, Cathrine ; Dhingra, Radhika ; Markunas, Christina A. ; Xu, Tao ; Reynolds, Lindsay M. ; Just, Allan C. ; Mandaviya, Pooja R. ; Ghantous, Akram ; Bennett, Brian D. ; Wang, Tianyuan ; Consortium, The Bios ; Bakulski, Kelly M. ; Melen, Erik ; Zhao, Shanshan ; Jin, Jianping ; Herceg, Zdenko ; Meurs, Joyce Van; Taylor, Jack A. ; Baccarelli, Andrea A. ; Murphy, Susan K. ; Liu, Yongmei ; Munthe-Kaas, Monica Cheng ; Deary, Ian J. ; Nystad, Wenche ; Waldenberger, Melanie ; Annesi-Maesano, Isabella ; Conneely, Karen ; Jaddoe, Vincent W.V. ; Arnett, Donna ; Snieder, Harold ; Kardia, Sharon L.R. ; Relton, Caroline L. ; Ong, Ken K. ; Ewart, Susan ; Moreno-Macias, Hortensia ; Romieu, Isabelle ; Sotoodehnia, Nona ; Fornage, Myriam ; Motsinger-Reif, Alison ; Koppelman, Gerard H. ; Bustamante, Mariona ; Levy, Daniel ; London, Stephanie J. - \ 2019
    Epigenomics 11 (2019)13. - ISSN 1750-1911 - p. 1487 - 1500.
    cigarette smoking - epigenetics - infant - maternal exposure - methylation

    Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.

    Theory of developmental origins of health and disease
    Kupers, Leanne - \ 2019
    child nutrition - pregnancy - epigenetics - disease prevention - disease incidence
    The first 1000 days of your (unborn) life play a crucial role in the risk of chronic diseases. But what if food is scarce?
    This lesson is part of the WageningenX MOOC called 'Nutrition, Heart Disease and Diabetes'.
    In utero sFlt-1 exposure differentially affects gene expression patterns in fetal liver
    Stojanovska, V. ; Holwerda, K.M. ; Graaf, A.M. Van Der; Verkaik-Schakel, R.N. ; Boekschoten, M.V. ; Faas, M.M. ; Scherjon, S.A. ; Plösch, T. - \ 2019
    Journal of Developmental Origins of Health and Disease 10 (2019)3. - ISSN 2040-1744 - p. 353 - 361.
    animal - developmental stage - epigenetics - fetus - general - molecular/cellular - small animals

    The soluble fms-like tyrosine kinase factor 1 (sFlt-1) is a major contributor to antiangiogenesis during preeclampsia. However, little is known about the effects of sFlt-1 on fetal health. In this study we aim to evaluate the effects of the sFlt-1 concentration during pregnancy on fetal liver physiology. We used adenoviral gene delivery in Sprague-Dawley dams (seven females, 10 weeks old) during mid-gestation (gestational day 8) with adenovirus overexpressing sFlt-1, and age-matched controls (six females, 10 weeks old) with empty adenoviral virus in order to quantify the sFlt-1 concentrations in pregnant dams. Dams exposed to adenoviral sFlt-1 delivery were subdivided into a low (n=4) and high sFlt-1 (n=3) group based on host response to the virus. One-way analysis of variance showed that fetuses (five per dam) exposed to high sFlt-1 concentrations in utero show fetal growth restriction (1.84±0.043 g high sFlt-1 v. 2.32±0.036 g control; mean (M)±s.e.m.; P<0.001), without hypertension or proteinuria in the dams. In continuation, the microarray analysis of the fetal liver of the high sFlt-1 group showed significant enrichment of key genes for fatty acid metabolism and Ppara targets. In addition, using pyrosequencing, we found that the Ppara enrichment in the high sFlt-1 group is accompanied by decreased methylation of its promoter (1.89±0.097 mean % methylation in high sFlt-1 v. 2.26±0.095 mean % methylation in control, M±s.e.m., P<0.02). Our data show that high sFlt-1 concentrations during pregnancy have detrimental effects on the fatty acid metabolism genes and the Ppara targets in the fetal liver.

    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: Genetic responsiveness of African buffalo to environmental stressors: a role for epigenetics in balancing autosomal and sex chromosome interactions?
    Hooft, W.F. van; Dougherty, Eric R. ; Getz, Wayne M. ; Greyling, Barend J. ; Zwaan, B.J. ; Bastos, Armanda D.S. - \ 2018
    Wageningen University & Research
    sex-ratio distorter - sex-ratio suppressor - sex-ratio adjustment - microsatellite - deleterious allele - sexually-antagonistic allele - African buffalo - Syncerus caffer - Kruger National Park - epigenetics - epigenetic modification - Y chromosome - frequency-dependent selection - bovine tuberculosis - body condition
    In the African buffalo (Syncerus caffer) population of the Kruger National Park (South Africa) a primary sex-ratio distorter and a primary sex-ratio suppressor have been shown to occur on the Y chromosome. A subsequent autosomal microsatellite study indicated that two types of deleterious alleles with a negative effect on male body condition, but a positive effect on relative fitness when averaged across sexes and generations, occur genome-wide and at high frequencies in the same population. One type negatively affects body condition of both sexes, while the other acts antagonistically: it negatively affects male but positively affects female body condition. Here we show that high frequencies of male-deleterious alleles are attributable to Y-chromosomal distorter-suppressor pair activity and that these alleles are suppressed in individuals born after three dry pre-birth years, likely through epigenetic modification. Epigenetic suppression was indicated by statistical interactions between pre-birth rainfall, a proxy for parental body condition, and the phenotypic effect of homozygosity/heterozygosity status of microsatellites linked to male-deleterious alleles, while a role for the Y-chromosomal distorter-suppressor pair was indicated by between-sex genetic differences among pre-dispersal calves. We argue that suppression of male-deleterious alleles results in negative frequency-dependent selection of the Y distorter and suppressor; a prerequisite for a stable polymorphism of the Y distorter-suppressor pair. The Y distorter seems to be responsible for positive selection of male-deleterious alleles during resource-rich periods and the Y suppressor for positive selection of these alleles during resource-poor periods. Male-deleterious alleles were also associated with susceptibility to bovine tuberculosis, indicating that Kruger buffalo are sensitive to stressors such as diseases and droughts. We anticipate that future genetic studies on African buffalo will provide important new insights into gene fitness and epigenetic modification in the context of sex-ratio distortion and infectious disease dynamics.
    Measuring stress-induced DNA methylation in apomictic Dandelions
    Gurp, Thomas P. van - \ 2017
    Wageningen University. Promotor(en): W.H. van der Putten, co-promotor(en): K.J.F. Verhoeven; A. Biere. - Wageningen : Wageningen University - ISBN 9789463436045 - 176
    taraxacum officinale - epigenetics - dna methylation - inheritance - apomixis - environmental factors - taraxacum officinale - epigenetica - dna-methylering - overerving - apomixis - milieufactoren

    The success or continuous existence of species requires continuous adaptation to changes in the environment to survive and contribute offspring to the next generation. Selection acts on the phenotype, which is in turn determined by the complex interplay of genetic, epigenetic and environmental variation. (Natural) selection leads to ‘survival of the fittest’ or best-adapted individuals to their local environment, ultimately determining which individuals contribute offspring to the next generation. Understanding the mechanisms by which epigenetic and genetic variation can arise and get passed on through generations determines our understanding of inheritance and evolution. Hitherto, the mechanistic understanding of genetics has shaped the scientific view of inheritance and evolution, leading to the gene-centered paradigm of Neo-Darwinism. However, recent studies indicate that besides genetic (DNA sequence) variation, epigenetic variation can also be transmitted between generations. Further studies on the properties and transgenerational dynamics of epigenetic variation are needed to enhance our understanding of heritability and evolution.

    Epigenetic variation has distinct properties and different transgenerational dynamics compared to genetic variation. Epigenetic variation helps to regulate gene expression and determines the different cell types and function in eukaryotes. The main function of DNA methylation, an important part of the epigenetic code, is to prevent the spread of selfish genetic elements in the genome and to establish the different cellular profiles observed in multicellular organisms. One differentiating feature of epigenetic variation compared to genetic variation is that (specific) epigenetic variation can arise under the influence of stress. This can enable a trans-generational stress-response of organisms which can have a positive influence on the phenotype and (natural) selection on either the (enhanced level of) transgenerational phenotypic plasticity or the epigenetic variation itself, potentially influencing natural selection and ultimately evolution. Where genetic variation can be characterized as hard-inheritance, the inheritance of epigenetic variation is often referred to as ‘soft-inheritance’ due to the lower transgenerational stability and resetting that occurs in the intergenerational transfer of epigenetic variation. Epigenetic variation is also often dependent on, or a downstream consequence, of genetic variation, suggesting that it is (in part) determined by genetic variation.

    Mechanistic studies in model species have contributed greatly to the understanding of the molecular mechanisms that control the dynamics of different epigenetic marks present in multicellular organisms. In plants, studies in the model plant Arabidopsis thaliana have resulted in deciphering the most important molecular mechanisms and actors, giving an ever-increasing insight into the dynamics of epigenetic regulation of cells and organisms. A key feature of model systems is the ability to ‘switch’ off certain genes or molecular pathways, for instance via the experimental use of mutants, enabling the study of their role in the heritability of epigenetic marks. DNA methylation is a well-studied epigenetic mark, which has shown high stability even in transgenerational experiments.

    From the perspective of studying epigenetic variation, plants are particularly interesting for several reasons, most importantly: 1) The separation between soma and germline, the Weismann barrier, is less strict in plants compared to other eukaryotes, as in higher plants

    germline cells are formed during floral development from somatic cells (which can occur throughout the life of the plant), whereas in most eukaryotes germline cell development is restricted to a defined point (early) in the organismal development. 2) The sessile nature of plants makes an adaptive plastic response to changing environments an important feature, a plant cannot just walk away when the going gets tough. 3) The transgenerational stability of DNA methylation is higher in plants compared to other eukaryotes such as mammals, in which epigenetic information is erased during germline reprogramming. These factors combined suggest that the potential importance of epigenetic variation in plants might be high.

    In this thesis, I focus on studying DNA methylation in apomictic Dandelions, applying Next Generation Sequencing (NGS) approaches to the study of this non-model plant species. Apomictic dandelions produce seeds that are genetically identical to the ‘mother’ plant, which makes it easier to study the influence of epigenetic variation without confounding effects of genetic variation. Working with Next Generation Sequencing data is still relatively new and therefore not always optimized for specific types of analysis. I discovered a distinct error pattern in RNAseq data that indicated an artificial source of variation that could be traced back to the way the RNAseq libraries were constructed. The first publication of this thesis contains a technical analysis of such artefacts present in RNAseq data, suggesting that these errors are related to random hexamer mispriming during library construction (Chapter 2).

    The main goal of my work is to better understand the role of epigenetic variation in adaptation and plasticity of plants. This role remains poorly understood. This is in part due to the lack of high-resolution techniques that allow for the detailed study of epigenetic marks such as DNA methylation in non-model organisms. Existing techniques for measuring DNA methylation such as methylation sensitive AFLPs offer only information on DNA methylation variation in an anonymous and limited fashion. The plummeting costs of sequencing techniques have enabled large-scale genotyping efforts (focusing on genetic variation only) for a wide variety of non-model organisms. Here, I extended this popular genotyping by sequencing technique, to allow for sequencing-based epigenotyping or epiGBS (chapter 3), which allows for measuring DNA methylation and genetic variation in hundreds of samples simultaneously. I have extensively validated the approach, providing evidence that with the right design, the accuracy of the DNA methylation measurements with epiGBS are as high as those with the gold standard Whole Genome Bisulfite Sequencing.

    An important aim of my PhD research was to investigate the stability of (stress induced) DNA methylation variation in apomictic dandelions and the potential of phenotypic variation underpinned by DNA methylation variation to be subjected to selection. I therefore studied the transgenerational stability of both stress induced and natural DNA methylation variation in different genotypes of apomictic dandelions in a six-generation experiment, comparing DNA methylation patterns between generations and tracking changes in them (chapter 4) using epiGBS. I found clear but limited evidence for environmental induction of heritable DNA methylation changes after application of Jasmonic Acid. Furthermore, I found a significant negative relation between the similarity of DNA methylation patterns and intergenerational distance, indicating epigenetic divergence over generations. I conclude that DNA methylation in both CG and CHG (where H can be any nucleotide except for G) sequence context are heritable and that environmental perturbation can result in heritable DNA methylation changes which are however not widespread.

    A prerequisite for epigenetic variation to contribute to adaptation is that epigenetic variants that affect the phenotype are heritable. To test whether an epigenetics-based selection response is possible, at least over the time course of a few generations, I selected early flowering for two subsequent generations in three genotypes of apomictic dandelions. This selection effort included lines that received a stress pre-treatment with either Jasmonic Acid or 5-azacytidine, to determine if stress-induced DNA methylation variation would increase the capacity to respond to selection. The selection experiment on flowering time (chapter 5) resulted in a shift in flowering time for all treatments in a young apomict, suggesting that natural and heritable epigenetic variation can underpin quantitative traits such as flowering time. I also found evidence for treatment induced (epi)genetic variation leading to a stronger selection response in one out of 3 genotypes. This suggests that stress- induced heritable epigenetic variation can lead to a selection response. Further study is however required to rule out genetic variants and to study the long-term stability of the variation selected upon.

    Finally, in the General Discussion I summarize the findings, putting them in context with recently published studies. I reflect on the state of the field of ecological epigenetics and in what sense the epiGBS technique that I developed and other emerging techniques can contribute to a better understanding of the role of epigenetic variation in ecology and evolution. I reflect on the place of epiGBS compared to other techniques. I point out that with the growing evidence of the inadequacy and misinterpretation of MS-AFLP results a systematic review of such results by replicating the studies employing sequencing based techniques such as epiGBS instead of MS-AFLP is in order.

    Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity
    Arts, Rob J.W. ; Novakovic, Boris ; Horst, Rob ter; Carvalho, Agostinho ; Bekkering, Siroon ; Lachmandas, Ekta ; Rodrigues, Fernando ; Silvestre, Ricardo ; Cheng, Shih Chin ; Wang, Shuang Yin ; Habibi, Ehsan ; Gonçalves, Luís G. ; Mesquita, Inês ; Cunha, Cristina ; Laarhoven, Arjan van; Veerdonk, Frank L. van de; Williams, David L. ; Meer, Jos W.M. van der; Logie, Colin ; O'Neill, Luke A. ; Dinarello, Charles A. ; Riksen, Niels P. ; Crevel, Reinout van; Clish, Clary ; Notebaart, Richard A. ; Joosten, Leo A.B. ; Stunnenberg, Hendrik G. ; Xavier, Ramnik J. ; Netea, Mihai G. - \ 2016
    Cell Metabolism 24 (2016)6. - ISSN 1550-4131 - p. 807 - 819.
    cholesterol metabolism - epigenetics - glutamine metabolism - glycolysis - trained immunity

    Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to β-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by β-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues.

    Epigenetic inheritance in apomictic dandelions : stress-induced and heritable modifications in DNA methylation and small RNA
    Preite, V. - \ 2016
    Wageningen University. Promotor(en): Wim van der Putten, co-promotor(en): K.J.F. Verhoeven. - Wageningen : Wageningen University - ISBN 9789462578715 - 152
    taraxacum officinale - epigenetics - inheritance - apomixis - dna methylation - rna - heritability - stress - taraxacum officinale - epigenetica - overerving - apomixis - dna-methylering - rna - heritability - stress

    Epigenetic variation, such as changes in DNA methylations, regulatory small RNAs (sRNAs) and chromatin modifications can be induced by environmental stress. There is increasing information that such induced epigenetic modifications can be transmitted to offspring, potentially mediating adaptive transgenerational responses to environmental changes. However, it is unclear if this phenomenon is common and relevant for adaptation under natural conditions. My thesis study aimed to examine epigenetic inheritance in common and widespread apomictic dandelions (Taraxacum officinale Wig.). Due to their asexual reproduction mode by producing clonal seeds offspring from seeds are genetically uniform and thus suitable to investigate epigenetic effects that are not confounded with genetic variation.

    I exposed apomictic dandelion lineages to drought and salicylic acid (SA) stress, which induces plant defense responses following pathogen attack, and found effects on patterns of DNA methylation up to two stress-free offspring generations after exposure. However, a heritable stress signal was not present in all tests and was stress- and lineage-dependent. Drought stress triggered a weak and lineage-dependent signal that was lost again in the second offspring generation. SA treatment revealed a stress-related increased rate of DNA methylation changes in the two offspring generations, but no stress signal was found in the stressed generation itself. I also observed changes in small RNA production due the drought and SA stress experienced two generations ago. These transgenerational sRNA effects showed association with gene functions related to grandparental drought and SA stress, which suggests functional relevance of the transgenerational effects.

    I used a reciprocal transplantation field experiment to investigate whether exposing dandelions to natural field stresses also triggers DNA methylation changes. The experiment revealed evidence of adaptive divergence between the populations, suggesting that non-native habitats are experienced as more stressful. However, under these field conditions no induction-based DNA methylation changes were found that persisted into offspring.

    By using AFLP and MS-AFLP screening of natural apomictic dandelion populations across a north-south transect in Europe I examined if natural, heritable DNA methylation variation reflects underlying genetic variation, or if it shows patterns that are not predictable from underlying genetics. I found that a large part of heritable DNA methylation differentiation along the north-south transect was correlated with genetic differentiation. However, a fraction of differentiation in heritable DNA methylation was independent from genetic variation. This suggests a potential of epigenetics to play an evolutionary role independently, at least to some extent, from underlying genetics. Overall, I found indications of epigenetic inheritance in apomictic dandelions. Whether epigenetic variation would result in adaptive phenotypic variation in nature and whether it would persist long enough to play a relevant role in adaptation remains unclear and requires further study.

    Persistent organic pollutants : aberrant DNA methylation underlying potential health effects
    Dungen, M.W. van den - \ 2016
    Wageningen University. Promotor(en): Tinka Murk; Ellen Kampman, co-promotor(en): Wilma Steegenga; Dieuwertje van Gils-Kok. - Wageningen : Wageningen University - ISBN 9789462577893 - 207
    persistent organic pollutants - dna methylation - molecular genetics - epigenetics - health hazards - toxic substances - endocrine disruptors - eels - fish consumption - toxicology - persistente organische verontreinigende stoffen - dna-methylering - moleculaire genetica - epigenetica - gezondheidsgevaren - toxische stoffen - hormoonverstoorders - palingen - visconsumptie - toxicologie

    Wild caught fish, especially marine fish, can contain high levels of persistent organic pollutants (POPs). In the Netherlands, especially eel from the main rivers have high POP levels. This led to a ban in 2011 on eel fishing due to health concerns. Many of the marine POPs have been related to adverse health effects such as endocrine disruption, neurodevelopmental problems, immune suppression and cancer. Although some mechanisms of action of POPs are clear, like dioxins binding to the aryl hydrocarbon receptor and OH-PCBs binding to thyroid transport proteins, not all adverse health effects can be explained by these mechanisms of action. Epigenetic phenomena, such as DNA methylation, have been proposed as a possible molecular mechanism underlying adverse health effects. DNA methylation is a heritable modification, which refers to the addition of a methyl group to cytosine in a CpG dinucleotide. Observational studies have indeed shown that POPs can affect global DNA methylation, although results are inconsistent. Some animal studies as well as in vitro experiments suggest that POPs can affect gene-specific DNA methylation, however, the biological significance and relevance for humans is not clear. Therefore, this thesis aimed to 1) study the accumulation of POPs in men consuming eel from high-polluted areas 2) elucidate whether seafood-related POPs can induce aberrant DNA methylation and 3) to determine whether DNA methylation is related to functional endpoints and gene expression in vitro.

    For this purpose eight POPs that are abundantly present in seafood were chosen, namely 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorobiphenyl (PCB) 126 and 153, perfluorooctanesulfonic acid (PFOS), hexabromocyclododecane (HBCD), 2,2′,4,4′- tetrabromodiphenyl ether (BDE-47), tributyltin (TBT), and methylmercury (MeHg). Chapter 2 describes the in vitro effects of these POPs and mixtures thereof in H295R adrenocortical carcinoma cells. Relative responses for 13 steroid hormones and 7 genes involved in the steroidogenic pathway, and CYP1A1, were analysed. PFOS induced the most pronounced effects on steroid hormone levels by significantly affecting 9 out of 13 hormone levels measured, with the largest increases found for 17β-estradiol, corticosterone, and cortisol. Furthermore, TCDD, both PCBs, and TBT significantly altered steroidogenesis. Increased steroid hormone levels were accompanied by related increased gene expression levels. The differently expressed genes were MC2R, CYP11B1, CYP11B2, and CYP19A1 and changes in gene expression levels were more sensitive than changes in hormone levels. The POP mixtures tested showed mostly additive effects, especially for DHEA and 17β-estradiol levels. This study shows that some seafood POPs are capable of altering steroidogenesis in H295R cells at concentrations that mixtures might reach in human blood, suggesting that adverse health effects cannot be excluded. DNA methylation was not measured in this study due to the short exposure time, which was expected not to be sufficient for long-term epigenetic marks. Therefore, in chapters 3A and 3B a differentiation experiment was performed enabling long-term exposure to POPs. Human mesenchymal stem cells (hMSCs) were differentiated into mature adipocytes over a time-course of 10 days. The transcriptional regulatory cascade involved in adipocyte differentiation has been extensively studied, however the mechanisms driving the transcription are poorly understood. In chapter 3A we therefore first explored the involvement of DNA methylation in transcriptional regulation during adipocyte differentiation. Genome-wide changes in DNA methylation were measured as well as the expression of adipogenic genes. The majority of these genes showed significant expression changes during the differentiation process. There were, however, only a couple of these differentially expressed genes that were differentially methylated. Genome-wide DNA methylation changes were most often located in intergenic regions, and underrepresented close to the transcription start site. This suggested that changes in DNA methylation are not the underlying mechanism regulating gene expression during adipocyte differentiation. Nevertheless, we explored DNA methylation differences after continuous exposure to POPs to investigate whether this could be an underlying mechanism by which POPs affect adipocyte differentiation. TCDD and PFOS decreased lipid accumulation, while TBT increased lipid accumulation. 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, but without concomitant gene expression changes. Differential methylation was again predominantly detected in intergenic regions, where the biological relevance of alterations in DNA methylation is unclear. This study demonstrated that POPs, at environmentally relevant levels, are able to induce differential DNA methylation in differentiating adipocytes. However, the biological relevance of this aberrant DNA methylation remains unclear.

    The in vitro results showed a proof of principle that POPs could be capable of altering DNA methylation. To this date, no human studies were performed investigating the relationship between POP levels and genome-wide DNA methylation. In order to investigate this, we first measured POP levels in eel consumers from the high-polluted areas (areas with a ban on eel fishing) and compared these levels to men consuming eel from low-polluted areas or aquaculture (chapter 4). We aimed to investigate the accumulation of these POPs and determine whether the predictions made in an earlier risk assessment were valid. This was indeed the case as levels of dioxins and dioxin-like compounds were on average 2.5 times higher in men consuming eel from high-polluted areas. Furthermore, PCBs with their hydroxylated metabolites, and perfluoroalkyl substances (PFASs) were, up to ten times, higher in these consumers. Especially the high levels of dioxins and dioxin-like compounds as well as the OH-PCBs are expected to be of health concern. We continued this research in chapter 5 by associating all the measured POPs to clinical parameters related to e.g. thyroid hormones and liver enzymes, but found no relationship. Subsequently, we investigated the association between dioxins and dioxin-like compounds, the sum of seven indicator PCBs, and PFOS with genome-wide DNA methylation. We detected a number of differentially methylated regions (DMRs) related to genes involved in carcinogenesis (e.g. BRCA1, MAGEE2, HOXA5), the immune system (e.g. RNF39, HLA-DQB1), in retinol homeostasis (DHRS4L2), or in metabolism (CYP1A1). In contrast to the in vitro data, most significant effects were detected in CpG islands and were annotated close to the promoter region. This suggests that the differential methylation might be related to differential expression and possibly induce adverse health effects. The hypermethylation of some of these gene related to cancer could be an explanation of the carcinogenic effects that are observed with POP exposure.

    Based on the results of this thesis we can conclude that the consumption of eel from high-polluted areas lead to accumulation of POPs above safe levels and that POP levels are associated with gene-specific DNA methylation in vitro as well as in environmentally exposed men. More research, however, is needed to fully elucidate the biological implications of this aberrant DNA methylation. A first step can be to measure histone modifications, as these two epigenetic marks together are likely better in predicting gene expression. The second step can be to investigate the potential health effects related to these epigenetic marks and to determine whether there is a causal relationship. Although at this point there is a lack of knowledge with regard to health effects caused by DNA methylation, the consumption of eel from these high-polluted areas is ill- advised, because adverse health effects cannot be excluded based on our results and can even be expected based on literature.

    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.

    Data from: Natural epigenetic variation contributes to heritable flowering divergence in a widespread asexual dandelion lineage
    Wilschut, Rutger ; Oplaat, C. ; Snoek, L.B. ; Kirschner, J. ; Verhoeven, K.J.F. - \ 2015
    Wageningen University & Research
    contemporary evolution - ecological genetics - plant mating systems - epigenetics
    Epigenetic variation has been proposed to contribute to the success of asexual plants, either as a contributor to phenotypic plasticity or by enabling transient adaptation via selection on transgenerationally stable, but reversible, epialleles. While recent studies in experimental plant populations have shown the potential for epigenetic mechanisms to contribute to adaptive phenotypes, it remains unknown whether heritable variation in ecologically relevant traits is at least partially epigenetically determined in natural populations. Here, we tested the hypothesis that DNA methylation variation contributes to heritable differences in flowering time within a single widespread apomictic clonal lineage of the common dandelion (Taraxacum officinale s. lat.). Apomictic clone members of the same apomictic lineage collected from different field sites showed heritable differences in flowering time, which was correlated with inherited differences in methylation-sensitive AFLP marker profiles. Differences in flowering between apomictic clone members were significantly reduced after in vivo demethylation using the DNA methyltransferase inhibitor zebularine. This synchronization of flowering times suggests that flowering time divergence within an apomictic lineage was mediated by differences in DNA methylation. While the underlying basis of the methylation polymorphism at functional flowering time-affecting loci remains to be demonstrated, our study shows that epigenetic variation contributes to heritable phenotypic divergence in ecologically relevant traits in natural plant populations. This result also suggests that epigenetic mechanisms can facilitate adaptive divergence within genetically uniform asexual lineages.
    Data from: Evidence from pyrosequencing indicates that natural variation in animal personality is associated with DRD4 DNA methylation
    Verhulst, E.C. ; Mateman, A.C. ; Zwier, Mathijs V. ; Caro, Samuel P. ; Verhoeven, K.J.F. ; Oers, Kees van - \ 2015
    Wageningen University & Research
    epigenetics - behaviour - personality - DNA methylation - birds
    Contain all the individual methylation levels per CpG position for assays A-D. Each tab ($data_$assay_$tissuetype) contains the results from one pyrosequence run and one type of tissue (blood or brain). The columns indicate: SampleID: bird sample Note: EEB score, F is Fast exploring, S is Slow exploring Pos. 1 Meth%: Methylation percentage for CpG position 1 in assayB Pos. 2 Meth%: Methylation percentage for CpG position 2 in assayB Etc. Cell colours indicate quality scores In green: highly reliable methylation scores In yellow: reliable methylation scores In pink: unreliable methylation scores (not used in downstream analyses) SampleID with *_replicate indicates that the DNA sample with this number was used in duplo on this plate for within assay analysis.
    Liver DNA methylation analysis in adult female C57BL/6JxFVB mice following perinatal exposure to bisphenol A
    Esterik, J.C. van; Vitins, A.P. ; Hodemaekers, H.M. ; Kamstra, J.H. ; Legler, J. ; Pennings, J.L.A. ; Steegenga, W.T. ; Lute, C. ; Jelinek, J. ; Issa, J.P. ; Dollé, M.E.T. ; Ven, L.T.M. van der - \ 2015
    Toxicology Letters 232 (2015)1. - ISSN 0378-4274 - p. 293 - 300.
    endocrine disruptors - disease - bpa - xenoestrogens - association - epigenetics - expression - nutrition - evolution - chemicals
    Bisphenol A (BPA) is a compound released from plastics and other consumer products used in everyday life. BPA exposure early in fetal development is proposed to contribute to programming of chronic diseases like obesity and diabetes, by affecting DNA methylation levels. Previously, we showed that in utero and lactational exposure of C57BL/6JxFVB hybrid mice via maternal feed using a dose range of 0–3000 µg/kg body weight/day resulted in a sex-dependent altered metabolic phenotype in offspring at 23 weeks of age. The most univocal effects were observed in females, with reduced body weights and related metabolic effects associated with perinatal BPA exposure. To identify whether the effects of BPA in females are associated with changes in DNA methylation, this was analyzed in liver, which is important in energy homeostasis. Measurement of global DNA methylation did not show any changes. Genome-wide DNA methylation analysis at specific CpG sites in control and 3000 µg/kg body weight/day females with the digital restriction enzyme analysis of methylation (DREAM) assay revealed potential differences, that could, however, not be confirmed by bisulfite pyrosequencing. Overall, we demonstrated that the observed altered metabolic phenotype in female offspring after maternal exposure to BPA was not detectably associated with liver DNA methylation changes. Still, other tissues may be more informative.
    Gezocht : chemische sporen van palingconsumptie
    Ramaker, R. ; Dungen, M.W. van den - \ 2014
    Resource: nieuwssite voor studenten en medewerkers van Wageningen UR 9 (2014)9. - ISSN 1389-7756 - p. 8 - 8.
    palingen - visconsumptie - voedselveiligheid - verontreinigd water - epigenetica - dioxinen - eels - fish consumption - food safety - polluted water - epigenetics - dioxins
    Onderzoeker wil honderd palingvissers voor onderzoek. Frequente palingeters geven mogelijk informatie over effect vervuiling.
    Genome-wide age-related changes in DNA methylation and gene expression in human PBMCs
    Steegenga, W.T. ; Boekschoten, M.V. ; Lute, C. ; Hooiveld, G.J.E.J. ; Groot, P.J. de; Morris, T.J. ; Teschendorff, A.E. ; Butcher, L.M. ; Beck, S. ; Müller, M.R. - \ 2014
    Age / the official journal of the American Aging Association 36 (2014)3. - ISSN 0161-9152 - p. 1523 - 1540.
    activated receptor-alpha - human brain - transcriptional profile - caloric restriction - stem-cells - promoter - cancer - epigenetics - disease - tissue
    Aging is a progressive process that results in the accumulation of intra- and extracellular alterations that in turn contribute to a reduction in health. Age-related changes in DNA methylation have been reported before and may be responsible for aging-induced changes in gene expression, although a causal relationship has yet to be shown. Using genome-wide assays, we analyzed age-induced changes in DNA methylation and their effect on gene expression with and without transient induction with the synthetic transcription modulating agent WY14,643. To demonstrate feasibility of the approach, we isolated peripheral blood mononucleated cells (PBMCs) from five young and five old healthy male volunteers and cultured them with or without WY14,643. Infinium 450K BeadChip and Affymetrix Human Gene 1.1 ST expression array analysis revealed significant differential methylation of at least 5 % (¿YO¿>¿5 %) at 10,625 CpG sites between young and old subjects, but only a subset of the associated genes were also differentially expressed. Age-related differential methylation of previously reported epigenetic biomarkers of aging including ELOVL2, FHL2, PENK, and KLF14 was confirmed in our study, but these genes did not display an age-related change in gene expression in PBMCs. Bioinformatic analysis revealed that differentially methylated genes that lack an age-related expression change predominantly represent genes involved in carcinogenesis and developmental processes, and expression of most of these genes were silenced in PBMCs. No changes in DNA methylation were found in genes displaying transiently induced changes in gene expression. In conclusion, aging-induced differential methylation often targets developmental genes and occurs mostly without change in gene expression.
    Missing heritability and soft inheritance of morphology and metabolism in Arabidopsis
    Kooke, R. - \ 2014
    Wageningen University. Promotor(en): Harro Bouwmeester; Joost Keurentjes, co-promotor(en): Dick Vreugdenhil. - Wageningen University : Wageningen University - ISBN 9789462570412 - 283
    arabidopsis - heritability - overerving - plantenmorfologie - metabolisme - plantenfysiologie - genetica - epigenetica - genetische variatie - arabidopsis - heritability - inheritance - plant morphology - metabolism - plant physiology - genetics - epigenetics - genetic variation

    The plant phenotype is shaped by complex interactions between its genotype and the environment. Although the genotype is stable and determined by the genomic sequence, plants are able to respond flexibly to changes in environmental conditions by orchestrated signal transduction pathways. The genomic sequence may change with each generation through chromosome rearrangements, meiotic recombination and spontaneous mutations. Through natural selection on these randomly induced changes, genotypes become adapted to their local environment. Because different genotypes adapt to different environments, natural variation within species expands in time and gives rise to a wide variety of genotypes and phenotypes. The genetic architecture that specifies the phenotype can be investigated by analyzing different genotypes in the same environment and associate the phenotypic variation with molecular markers that discriminate the genotypes. Recent advances in next-generation sequencing technology enabled the fast sequencing of entire genomes, and in Arabidopsisthalianaalone, more than 1000 different genotypes have been fully resequenced. The sequencing allows the association of phenotypic variation with large numbers of single nucleotide polymorphisms (SNPs) that greatly enhance resolution in genome-wide association studies (GWAS).

    GWAS on human diseases suffer from missing heritability that is most likely caused by the genetic architecture of the disease traits. Many variants of small effect or rare variants most likely determine a large part of the genetic variation and these variants are difficult to identify in GWAS due to lack of statistical power. In plants, several GWAS have been performed and they have identified previously validated genes and genes involved in monogenic disease resistance, but elucidating quantitative traits such as many agronomic important traits might be problematic in plants as well. Chapter 2 describes a GWA study in which quantitative morphological traits, such as leaf area, flowering time and branching were examined in 350 accessions of Arabidopsis for association with about 200,000 SNPs. The morphological traits showed extensive variation and were highly heritable, but GWA mapping could not identify the genetic variants that explain the heritability. Therefore, missing heritability was addressed using genomic selection models and these models confirmed the quantitative complex architecture of the morphological traits. Based upon these results, the heritability was assumed to be hidden below the significance threshold, and indeed lowering the significance threshold enabled the identification of many candidate genes that have been implicated to play a role in the phenotype directly or indirectly, in previous studies. One candidate gene was studied in more detail; natural variants of ACS11, an ethylene biosynthesis gene, associated significantly with the petiole to leaf length ratio. ACS11is indeed expressed in petioles and ectopically supplied ethylene abolished the difference in the phenotype of natural variants at this locus, strongly suggesting that ACS11is involved in the regulation of petiole growth.

    However, lowering the significance threshold also increases the number of false-positive associations, non-causal alleles that co-segregate with the trait values. Because regulation of the morphological traits occurs at multiple intermediate levels, increased certainty on the associations can be obtained by performing GWA mapping on the intermediate levels from genotype to phenotype such as gene expression, and protein and metabolite content. Chapter 3 describes a literature survey into the multi-dimensional regulation of metabolic networks that are regulated by inputs from the clock, the communication between cells and between source and sink tissues, and the environment. The metabolic status of the plant can be seen as the final product of the interaction with the environment, and as such, it can serve as a blueprint for growth and development. Chapter 4 describes the abundant variation in enzyme activities and metabolites involved in primary carbon and nitrogen metabolism. The metabolite and enzyme activity data were analyzed together with plant biomass data, and many pleiotropic regulators were identified with opposite effects on primary metabolism and biomass formation. Natural variants in two stress-responsive genes were oppositely associated with biomass and many enzymes and metabolites involved in primary metabolism, suggesting that higher enzyme activities and higher levels of sugars and proteins might be needed to support plant resistance to stress at the expense of growth.

    Some studies indicated that epigenetic variation, independent of the genetic SNPs, may contribute to missing heritability. Epigenetic inheritance is defined as the inheritance of phenotypic variation to future generations without changes in DNA sequence. Epigenetic variation is caused by variation in chromatin marks such as DNA methylation, histone modifications and small RNAs. Recently, a recombinant inbred line (RIL) population was developed in Arabidopsis where the chromosomes are differentially methylated in lines with an otherwise isogenic background by crossing wild-type Col-0 with a hypomethylated ddm1-2mutant. Chapter 5 describes the epigenetic regulation of morphology and phenotypic plasticity by studying morphological variation in 99 epiRILs under control and saline conditions. The morphology and plasticity trait values were associated with differentially methylated regions (DMRs) that were used as molecular markers in QTL mapping. Many QTLs for various morphological traits and phenotypic plasticity parameters co-located, suggesting pleiotropic epigenetic regulation of growth, morphology and plasticity. Furthermore, methylation variation in the promoter of a salt-tolerance gene, HIGH-AFFINITY K+TRANSPORTER1 (HKT1)associated significantly with leaf area, especially under saline conditions.

    To gain more insight into the epigenetic regulation of plant growth and morphology, chapter 6 describes the epigenetic regulation of secondary metabolite levels in leaves and flowers and studies the relationship with the morphological traits determined in chapter 5. Many of the QTLs that were found for growth and morphology overlapped with the QTLs for metabolic traits, and suggest pleiotropic regulation. Furthermore, subsets of the metabolites correlated well with the morphological traits and might thus be regulated by the same loci. The majority of metabolite QTLs was detected for glucosinolates and flavonoids in the flowers, and methylation variation was observed for some of the biosynthetic pathway genes of these compounds when comparing Col-0 and ddm1-2, which indicates a role for epigenetic regulation of these biosynthesis pathways.

    Although stable, natural epialleles have been found in plant species and the environment can induce hypo- and hypermethylation of DNA, it remains elusive whether environmentally-induced epigenetic changes can be inherited to subsequent generations, independent of genetic variation. Chapter 7 describes the transgenerational inheritance of phenotypic variation in progeny derived from a common Arabidopsis founder line. The progeny of stressed parents and grandparents showed variation in morphological traits, metabolite accumulation and gene expression. For example, many salt-responsive genes were up-regulated in progeny of salt-stressed grandparents. The responses to biotic (methyljasmonate) and abiotic (salt) stress differed strongly and this suggests that different environments can cause different transgenerational responses. Because all lines are derived from a single ancestor, epigenetic variation and not DNA variation is most likely causal for the phenotypic variation. Further studies are, however, needed to provide conclusive evidence for transgenerational inheritance.

    Chapter 8 provides a synthesis of the work and discusses the GWA studies in the light of missing heritability, genetic architecture and the verification of candidate genes. The work on epigenetic regulation of phenotypic plasticity, morphology and metabolism is discussed in relation to Lamarckian soft inheritance that gained new enthusiasm after some recent discoveries in the field of epigenetics. And finally, the metabolomics work is discussed in the light of the growth-defense hypothesis that states that investments in defense occur at the expense of growth.

    'Je moeder leert je wie je vijanden zijn'
    Makkink, C. ; Parmentier, H.K. - \ 2014
    De Molenaar 2014 (2014)7. - ISSN 0165-4284 - p. 26 - 27.
    vleeskuikenouderdieren - immuunsysteem - immuniteitsreactie - epigenetica - diervoeding - broiler breeders - immune system - immune response - epigenetics - animal nutrition
    Via de voeding van ouderdieren kan de werking van het immuunsysteem van de nakomelingen worden beïnvloed. Het is een uitdaging om interventies te vinden die het immuunsysteem van landbouwhuisdieren optimaliseren, zo luidde de conclusie tijdens de Feed4Foodure-themamiddag.
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