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.

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    Correction to: Rewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein
    Keating, Samuel T. ; Groh, Laszlo ; Thiem, Kathrin ; Bekkering, Siroon ; Li, Yang ; Matzaraki, Vasiliki ; Heijden, Charlotte D.C.C. van der; Puffelen, Jelmer H. van; Lachmandas, Ekta ; Jansen, Trees ; Oosting, Marije ; Bree, L.C.J. de; Koeken, Valerie A.C.M. ; Moorlag, Simone J.C.F.M. ; Mourits, Vera P. ; Diepen, Janna van; Stienstra, Rinke ; Novakovic, Boris ; Stunnenberg, Hendrik G. ; Crevel, Reinout van; Joosten, Leo A.B. ; Netea, Mihai G. ; Riksen, Niels P. - \ 2020
    Journal of Molecular Medicine 98 (2020). - ISSN 0946-2716

    The correct name of the 17th Author is presented in this paper. In the paragraph “Metabolic analysis” of the Method section “an XFp Analyzer” should be changed to “an XFe96 Analyzer”.

    Rewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein
    Keating, Samuel T. ; Groh, Laszlo ; Thiem, Kathrin ; Bekkering, Siroon ; Li, Yang ; Matzaraki, Vasiliki ; Heijden, Charlotte D.C.C. van der; Puffelen, Jelmer H. van; Lachmandas, Ekta ; Jansen, Trees ; Oosting, Marije ; Bree, L.C.J. de; Koeken, Valerie A.C.M. ; Moorlag, Simone J.C.F.M. ; Mourits, Vera P. ; Diepen, Janna van; Stienstra, Rinke ; Novakovic, Boris ; Stunnenberg, Hendrik G. ; Crevel, Reinout van; Joosten, Leo A.B. ; Netea, Mihai G. ; Riksen, Niels P. - \ 2020
    Journal of Molecular Medicine 98 (2020). - ISSN 0946-2716 - p. 819 - 831.
    Atherosclerosis - Cardiovascular disease - Diabetes complications - Glycolysis - Immunometabolism - Inflammation - Trained immunity

    Abstract: Stimulation of monocytes with microbial and non-microbial products, including oxidized low-density lipoprotein (oxLDL), induces a protracted pro-inflammatory, atherogenic phenotype sustained by metabolic and epigenetic reprogramming via a process called trained immunity. We investigated the intracellular metabolic mechanisms driving oxLDL-induced trained immunity in human primary monocytes and observed concomitant upregulation of glycolytic activity and oxygen consumption. In two separate cohorts of healthy volunteers, we assessed the impact of genetic variation in glycolytic genes on the training capacity of monocytes and found that variants mapped to glycolytic enzymes PFKFB3 and PFKP influenced trained immunity by oxLDL. Subsequent functional validation with inhibitors of glycolytic metabolism revealed dose-dependent inhibition of trained immunity in vitro. Furthermore, in vivo administration of the glucose metabolism modulator metformin abrogated the ability for human monocytes to mount a trained response to oxLDL. These findings underscore the importance of cellular metabolism for oxLDL-induced trained immunity and highlight potential immunomodulatory strategies for clinical management of atherosclerosis. Key messages: Brief stimulation of monocytes to oxLDL induces a prolonged inflammatory phenotype.This is due to upregulation of glycolytic metabolism.Genetic variation in glycolytic genes modulates oxLDL-induced trained immunity.Pharmacological inhibition of glycolysis prevents trained immunity.

    The Hematopoietic Transcription Factors RUNX1 and ERG Prevent AML1-ETO Oncogene Overexpression and Onset of the Apoptosis Program in t(8;21) AMLs
    Mandoli, Amit ; Singh, Abhishek A. ; Prange, Koen H.M. ; Tijchon, Esther ; Oerlemans, Marjolein ; Dirks, Rene ; Huurne, Menno Ter; Wierenga, Albertus T.J. ; Janssen-Megens, Eva M. ; Berentsen, Kim ; Sharifi, Nilofar ; Kim, Bowon ; Matarese, Filomena ; Nguyen, Luan N. ; Hubner, Nina C. ; Rao, Nagesha A. ; Akker, Emile van den; Altucci, Lucia ; Vellenga, Edo ; Stunnenberg, Hendrik G. ; Martens, Joost H.A. - \ 2016
    Cell Reports 17 (2016)8. - ISSN 2211-1247 - p. 2087 - 2100.
    acute myeloid leukemia - AML1-ETO - apoptosis - epigenome - iPSC - RUNX1

    The t(8;21) acute myeloid leukemia (AML)-associated oncoprotein AML1-ETO disrupts normal hematopoietic differentiation. Here, we have investigated its effects on the transcriptome and epigenome in t(8,21) patient cells. AML1-ETO binding was found at promoter regions of active genes with high levels of histone acetylation but also at distal elements characterized by low acetylation levels and binding of the hematopoietic transcription factors LYL1 and LMO2. In contrast, ERG, FLI1, TAL1, and RUNX1 bind at all AML1-ETO-occupied regulatory regions, including those of the AML1-ETO gene itself, suggesting their involvement in regulating AML1-ETO expression levels. While expression of AML1-ETO in myeloid differentiated induced pluripotent stem cells (iPSCs) induces leukemic characteristics, overexpression increases cell death. We find that expression of wild-type transcription factors RUNX1 and ERG in AML is required to prevent this oncogene overexpression. Together our results show that the interplay of the epigenome and transcription factors prevents apoptosis in t(8;21) AML cells.

    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.

    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.

    Dynamics of gene silencing during X inactivation using allele-specific RNA-seq
    Marks, Hendrik ; Kerstens, Hindrik H.D. ; Barakat, Tahsin Stefan ; Splinter, Erik ; Dirks, René A.M. ; Mierlo, Guido van; Joshi, Onkar ; Wang, Shuang Yin ; Babak, Tomas ; Albers, Cornelis A. ; Kalkan, Tüzer ; Smith, Austin ; Jouneau, Alice ; Laat, Wouter de; Gribnau, Joost ; Stunnenberg, Hendrik G. - \ 2015
    Genome Biology 16 (2015)1. - ISSN 1474-7596

    Background: During early embryonic development, one of the two X chromosomes in mammalian female cells is inactivated to compensate for a potential imbalance in transcript levels with male cells, which contain a single X chromosome. Here, we use mouse female embryonic stem cells (ESCs) with non-random X chromosome inactivation (XCI) and polymorphic X chromosomes to study the dynamics of gene silencing over the inactive X chromosome by high-resolution allele-specific RNA-seq. Results: Induction of XCI by differentiation of female ESCs shows that genes proximal to the X-inactivation center are silenced earlier than distal genes, while lowly expressed genes show faster XCI dynamics than highly expressed genes. The active X chromosome shows a minor but significant increase in gene activity during differentiation, resulting in complete dosage compensation in differentiated cell types. Genes escaping XCI show little or no silencing during early propagation of XCI. Allele-specific RNA-seq of neural progenitor cells generated from the female ESCs identifies three regions distal to the X-inactivation center that escape XCI. These regions, which stably escape during propagation and maintenance of XCI, coincide with topologically associating domains (TADs) as present in the female ESCs. Also, the previously characterized gene clusters escaping XCI in human fibroblasts correlate with TADs. Conclusions: The gene silencing observed during XCI provides further insight in the establishment of the repressive complex formed by the inactive X chromosome. The association of escape regions with TADs, in mouse and human, suggests that TADs are the primary targets during propagation of XCI over the X chromosome.

    The mode of inheritance in tetraploid cut roses
    Koning-Boucoiran, C.F.S. ; Gitonga, V.W. ; Yan, Z. ; Dolstra, O. ; Linden, C.G. van der; Schoot, J. van der; Uenk-Stunnenberg, G.E. ; Verlinden, K. ; Smulders, M.J.M. ; Krens, F.A. ; Maliepaard, C.A. - \ 2012
    Theoretical and Applied Genetics 125 (2012)3. - ISSN 0040-5752 - p. 591 - 607.
    genetic diversity analysis - microsatellite markers - morphological markers - diploid fragaria - linkage maps - allopolyploids - polyploids - resistance - plant - aflp
    Tetraploid hybrid tea roses (Rosa hybrida) represent most of the commercial cultivars of cut roses and form the basis for breeding programmes. Due to intensive interspecific hybridizations, modern cut roses are complex tetraploids for which the mode of inheritance is not exactly known. The segregation patterns of molecular markers in a tetraploid mapping population of 184 genotypes, an F1 progeny from a cross of two heterozygous parents, were investigated for disomic and tetrasomic inheritance. The possible occurrence of double reduction was studied as well. We can exclude disomic inheritance, but while our observations are more in line with a tetrasomic inheritance, we cannot exclude that there is a mixture of both inheritance modes. Two novel parental tetraploid linkage maps were constructed using markers known from literature, combined with newly generated markers. Comparison with the integrated consensus diploid map (ICM) of Spiller et al. (Theor Appl Genet 122:489–500, 2010) allowed assigning numbers to each of the linkage groups of both maps and including small linkage groups. So far, the possibility of using marker-assisted selection in breeding of tetraploid cut roses and of other species with a tetrasomic or partly tetrasomic inheritance, is still limited due to the difficulties in establishing marker-trait associations. We used these tetraploid linkage maps to determine associations between markers, two morphological traits and powdery mildew resistance. The knowledge on inheritance and marker-trait associations in tetraploid cut roses will be of direct use to cut rose breeding.
    Construction of an integrated microsatellite and key morphological characteristic database of potato varieties on the EU common catalogue
    Reid, A. ; Hof, L. ; Felix, G. ; Rucker, B. ; Tams, S. ; Milczynska, E. ; Esselink, G. ; Uenk-Stunnenberg, G.E. ; Vosman, B. ; Weitz, A. - \ 2011
    Euphytica 182 (2011)2. - ISSN 0014-2336 - p. 239 - 249.
    identification - markers - tomato - plants
    The European Union Common Catalogue (EUCC) for potato contains over 1000 varieties. Each year member states add varieties to the list after they have undergone Distinctness, Uniformity and Stability (DUS) testing according to international guidelines. A rapid and robust method for variety identification to aid the management and maintenance of existing variety collections and for the screening of new candidate varieties would therefore be a highly useful tool for DUS testing stations. A database containing key morphological characteristics and microsatellite data was constructed for varieties on the 2006 list of the EUCC for potato. Rules for scoring SSR markers in different laboratories were established to allow a harmonized scoring of markers. Almost all varieties (99.5%) were shown to have unique molecular profiles and in pair wise comparisons 99.99% of all variety pairs could be distinguished. This clearly shows the versatility of the markers and database for identifying potato samples.
    Peroxisome Proliferator-activated Receptor gamma Regulates Expression of the Anti-lipolytic G-protein-coupled Receptor 81 (GPR81/Gpr81)
    Jeninga, E.H. ; Bugge, A. ; Nielsen, R. ; Kersten, A.H. ; Hamers, N. ; Dani, C. ; Wabitsch, M. ; Berger, R. ; Stunnenberg, H.G. ; Mandrup, S. ; Kalkhoven, E. - \ 2009
    Journal of Biological Chemistry 284 (2009)39. - ISSN 0021-9258 - p. 26385 - 26393.
    nicotinic-acid receptor - type-2 diabetes-mellitus - mature 3t3-l1 adipocytes - necrosis-factor-alpha - human adipose-tissue - free fatty-acids - ppar-gamma - puma-g - insulin-resistance - molecular-identification
    The ligand-inducible nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) plays a key role in the differentiation, maintenance, and function of adipocytes and is the molecular target for the insulin-sensitizing thiazoledinediones (TZDs). Although a number of PPAR gamma target genes that may contribute to the reduction of circulating free fatty acids after TZD treatment have been identified, the relevant PPAR gamma target genes that may exert the anti-lipolytic effect of TZDs are unknown. Here we identified the anti-lipolytic human G-protein-coupled receptor 81 (GPR81), GPR109A, and the (human-specific) GPR109B genes as well as the mouse Gpr81 and Gpr109A genes as novel TZD-induced genes in mature adipocytes. GPR81/Gpr81 is a direct PPAR gamma target gene, because mRNA expression of GPR81/Gpr81 (and GPR109A/Gpr109A) increased in mature human and murine adipocytes as well as in vivo in epididymal fat pads of mice upon rosiglitazone stimulation, whereas small interfering RNA-mediated knockdown of PPAR gamma in differentiated 3T3-L1 adipocytes showed a significant decrease in Gpr81 protein expression. In addition, chromatin immunoprecipitation sequencing analysis in differentiated 3T3-L1 cells revealed a conserved PPAR: retinoid X receptor-binding site in the proximal promoter of the Gpr81 gene, which was proven to be functional by electromobility shift assay and reporter assays. Importantly, small interfering RNA-mediated knockdown of Gpr81 partly reversed the inhibitory effect of TZDs on lipolysis in 3T3-L1 adipocytes. The coordinated PPAR gamma-mediated regulation of the GPR81/Gpr81 and GPR109A/Gpr109A genes (and GPR109B in humans) presents a novel mechanism by which TZDs may reduce circulating free fatty acid levels and perhaps ameliorate insulin resistance in obese patients.
    Expressed sequence tag-derived microsatellite markers of perennial ryegrass (Lolium perenne L.).
    Studer, B. ; Asp, T. ; Frei, U. ; Hentrup, S. ; Meally, H. ; Guillard, A. ; Barth, S. ; Muylle, H. ; Roldan-Ruiz, I. ; Barre, P. ; Boucoiran, C.F.S. ; Stunnenberg, G. ; Dolstra, O. ; Skot, L. ; Skot, K.P. ; Turner, B. ; Humphreys, M. ; Kolliker, R. ; Roulund, N. ; Nielsen, K.K. ; Lubberstedt, T. - \ 2008
    Molecular Breeding 21 (2008)4. - ISSN 1380-3743 - p. 533 - 548.
    repeat ssr markers - multiflorum lam. - linkage map - plants - transferability - construction - reveals - qtl
    An expressed sequence tag (EST) library of the key grassland species perennial ryegrass (Lolium perenne L.) has been exploited as a resource for microsatellite marker development. Out of 955 simple sequence repeat (SSR) containing ESTs, 744 were used for primer design. Primer amplification was tested in eight genotypes of L. perenne and L. multiflorum representing (grand-) parents of four mapping populations and resulted in 464 successfully amplified EST-SSRs. Three hundred and six primer pairs successfully amplified products in the mapping population VrnA derived from two of the eight genotypes included in the original screening and revealed SSR polymorphisms for 143 ESTs. Here, we report on 464 EST-derived SSR primer sequences of perennial ryegrass established in laboratory assays, providing a dedicated tool for marker assisted breeding and comparative mapping within and among forage and turf grasses. Electronic supplementary material The online version of this article (doi:10.1007/s11032-007-9148-0) contains supplementary material, which is available to authorized users.
    Discontinuous transcription and RNA processing of vaccinia virus late messengers results in a 5' poly(A) leader.
    Schwer, B. ; Visca, P. ; Vos, J.C. ; Stunnenberg, H.G. - \ 1987
    Cell 50 (1987). - ISSN 0092-8674 - p. 163 - 169.
    Effect of alfa-amanitin and actinomycin D on RNA synthesis in the protoplasts of Aspergillus nidulans
    Stunnenberg, H.G. ; Broek, H.W.J. van den - \ 1982
    Microbios 35 (1982). - ISSN 0026-2633 - p. 197 - 207.
    DNA-dependent RNA polymerases from the fungus Aspergillus nidulans
    Stunnenberg, H.G. - \ 1981
    Landbouwhogeschool Wageningen. Promotor(en): J.H. van der Veen. - Wageningen : Stunnenberg - 128
    aspergillus - moleculaire genetica - transcriptie - aspergillus - molecular genetics - transcription
    The aim of the work presented here was the isolation and characterization of the DNA-dependent RNA polymerases from the fungus Aspergillus nidulans, which was a part of a project concerning the regulation of gene expression in this lower eukaryote.

    The transcription of a genome and the regulation mechanisms involved are basic steps in the development and differentiation of an organism. The regulation mechanisms necessary for the development of a single fertilized egg cell into an organism like men, must be very precise and complicated, if one considers that the organism consists of dozens of different cell types, each having a specific function as part of the whole. The signals, which trigger a cell to develop into a highly specialized blood or brain cell, are largely unknown at the moment. Because the developmental and differentiation process in higher eukaryotes is so complex, relatively simple differentiating organisms, like Aspergillus nidulans may be more suitable for the study of the molecular mechanisms underlying the developmental regulation of gene expression. The limited knowledge of the biochemical organization of Aspergillus, as compared to a lower eukaryote like yeast, is certainly a disadvantage, but at the same time a challenge for the investigator. On the other hand, the genetics of Aspergillus has been extensively studied and this can be of great use in biochemical and developmental studies of this organism.

    The transcription of coding sequences of the DNA into RNA, is one of the first processes of a complex chain of events underlying the expression of genetic information. The specific mechanisms involved in the regulation of transcription are largely unknown, but they must directly or indirectly affect the activity of the DNA-dependent RNA polymerases, responsible for the differential transcription of genetic information. Apart from the regulation at the cellular level of the enzyme, other mechanisms must be responsible for the differential transcription of specific classes of genes, that are transcribed by a common enzyme. Structural modification of the chromatin could influence the accessibility of specific genes and hence their ability to be transcribed by an RNA polymerase. Transcription may also be controlled directly by regulators, altering the interaction between the enzyme and a specific gene or genes. It is therefore important to purify eukaryotic nuclear RNA polymerases and to study their structure and function. For understanding the actual transcription mechanism, the development and study of cell-free systems, supplemented with purified RNA polymerases and well characterized templates, will be required.

    This thesis describes how the DNA-dependent RNA polymerases I and II from Aspergillus nidulans can be successfully purified and subsequently characterized with respect to their catalytic properties and subunit composition (Chapters 2 and 3). Preparation of protoplasts from Aspergillus (Chapter 4) was initally thought to be necessary for the isolation of the RNA polymerases, because desintegration of the rigid cell wall of Aspergillus was the first difficulty encountered. Although large amounts of protoplasts could be prepared, the procedure appeared to be rather timeconsuming and impractical as a standard, large-scale procedure for the isolation of the RNA polymerases. Protoplasts, however, can be very useful when micro-assays or a gentle treatment to break open the cell wall are required. This is demonstrated in Chapter 5, where the effect of inhibitors of RNA synthesis has been studied in vivo in metabolically active protoplasts. The isolation and characterization of RNA polymerase III could not be achieved within the limited time available for the project.

    An alpha-amanitin-resistant DNA-dependent RNA polymerase II from the fungus Aspergillus nidulans
    Stunnenberg, H.G. ; Wennekes, L.M.J. ; Spierings, T. ; Broek, H.W.J. van den - \ 1981
    European Journal of Biochemistry 117 (1981). - ISSN 0014-2956 - p. 121 - 129.
    RNA polymerases from the fungus aspergillus nidulans
    Stunnenberg, H.G. ; Wennekes, L.M.J. ; Broek, H.W.J. van den - \ 1979
    In: Abstr. XIth Intern. Congress Biochemistry, Toronto, 1979
    Largescale purification of RNA polymerase I from the fungus Aspergillus nidulans
    Stunnenberg, H.G. ; Wennekes, L.M.J. ; Broek, H.W.J. van den - \ 1979
    In: Abstr. Special FEBS Meeting on Enzymes, Dubrovnick (1979)
    RNA polymerase from the fungus Aspergillus nidulans. Largescale purification of DNA-dependent RNA polymerase I (or A)
    Stunnenberg, H.G. ; Wennekes, L.M.J. ; Broek, H.W.J. van den - \ 1979
    European Journal of Biochemistry 98 (1979). - ISSN 0014-2956 - p. 107 - 119.
    Protoplasts from Aspergillus nidulans
    Broek, H.W.J. van den; Stunnenberg, H.G. ; Wennekes, L.M.J. - \ 1979
    Microbios 26 (1979). - ISSN 0026-2633 - p. 115 - 128.
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