126 results on '"van IJcken W"'
Search Results
2. Germline variant in MSX1 identified in a Dutch family with clustering of Barrett’s esophagus and esophageal adenocarcinoma
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van Nistelrooij, A. M. J., van Marion, R., van Ijcken, W. F. J., de Klein, A., Wagner, A., Biermann, K., Spaander, M. C. W., van Lanschot, J. J. B., Dinjens, W. N. M., and Wijnhoven, B. P. L.
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- 2018
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3. Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms
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Amin, N, Jovanova, O, Adams, H H H, Dehghan, A, Kavousi, M, Vernooij, M W, Peeters, R P, de Vrij, F M S, van der Lee, S J, van Rooij, J G J, van Leeuwen, E M, Chaker, L, Demirkan, A, Hofman, A, Brouwer, R W W, Kraaij, R, Willems van Dijk, K, Hankemeier, T, van Ijcken, W F J, Uitterlinden, A G, Niessen, W J, Franco, O H, Kushner, S A, Ikram, M A, Tiemeier, H, and van Duijn, C M
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- 2017
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4. Exploring the Interspecific Interactions and the Metabolome of the Soil Isolate Hylemonella gracilis.
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Tyc, Olaf, Kulkarni, Purva, Ossowicki, Adam, Tracanna, Vittorio, Medema, Marnix H., Baarlen, Peter van, van IJcken, W. F. J., Verhoeven, Koen J. F., and Garbeva, Paolina
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- 2023
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5. Exploring the Interspecific Interactions and the Metabolome of the Soil Isolate Hylemonella gracilis.
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Tyc, Olaf, Kulkarni, Purva, Ossowicki, Adam, Tracanna, Vittorio, Medema, Marnix H., van Baarlen, Peter, van IJcken, W. F. J., Verhoeven, Koen J. F., and Garbeva, Paolina
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- 2022
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6. Employed family-based genetic discovery combining linkage analysis and exome sequencing to identify RCL1 as a novel candidate gene for depression, with independent replication in a population-based cohort
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Amin, N, de Vrij, F M S, Baghdadi, M, Brouwer, R W W, van Rooij, J G J, Jovanova, O, Uitterlinden, A G, Hofman, A, Janssen, H L A, Murad, S Darwish, Kraaij, R, Stedehouder, J, van den Hout, M C G N, Kros, J M, van IJcken, W F J, Tiemeier, H, Kushner, S A, and van Duijn, C M
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- 2018
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7. miR-141 regulates KEAP1 and modulates cisplatin sensitivity in ovarian cancer cells
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van Jaarsveld, M T M, Helleman, J, Boersma, A W M, van Kuijk, P F, van IJcken, W F, Despierre, E, Vergote, I, Mathijssen, R H J, Berns, E M J J, Verweij, J, Pothof, J, and Wiemer, E A C
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- 2013
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8. Discovery of new microRNAs by small RNAome deep sequencing in childhood acute lymphoblastic leukemia
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Schotte, D, Moqadam, F Akbari, Lange-Turenhout, E A M, Chen, C, van IJcken, W F J, Pieters, R, and den Boer, M L
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- 2011
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9. Regulated genes in psoriatic skin during treatment with fumaric acid esters
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Onderdijk, A. J., Balak, D. M.W., Baerveldt, E. M., Florencia, E. F., Kant, M., Laman, J. D., van IJcken, W. F.J., Racz, E., de Ridder, D., Thio, H. B., and Prens, E. P.
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- 2014
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10. The dystrophin gene and cognition in the cognitively healthy population: EP4249
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Vojinovic, D., Adams, H. H., van der Lee, S. J., Ibrahim-Verbaas, C. A., Brouwer, R., van den Hout, M. C.G.N., Oole, E., van Rooij, J., Uitterlinden, A., Hofman, A., van IJcken, W., Aartsma-Rus, A., van Ommen, G. B., Ikram, M. A., van Duijn, C. M., and Amin, N.
- Published
- 2014
11. Erratum: Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms
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Amin, N, Jovanova, O, Adams, H H H, Dehghan, A, Kavousi, M, Vernooij, M W, Peeters, R P, de Vrij, F M S, van der Lee, S J, van Rooij, J G J, van Leeuwen, E M, Chaker, L, Demirkan, A, Hofman, A, Brouwer, R W W, Kraaij, R, Willems van Dijk, K, Hankemeier, T, van Ijcken, W F J, Uitterlinden, A G, Niessen, W J, Franco, O H, Kushner, S A, Ikram, M A, Tiemeier, H, and van Duijn, C M
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- 2017
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12. Microtubule plus-end tracking protein CLASP2 KO mice phenocopy CAMT: a role for CLASP2 in hematopoiesis and hematopoietic stem cell maintenance: PA 2.04–1
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Gutierrez, L, Drabek, D, Robin, C, Galjart, N, Vermeij, M, Clapes, T, Patel, S R, Boisset, J-C, Van Haren, J, Pereira, A L, Liu, Z, Akinci, U, Nikolic, T, Van Ijcken, W, Van Den Hout, M, Meinders, M, Melo, C, Sambade, C, Drabek, K, Hendriks, R W, Philipsen, S, Mommaas, M, Grosveld, F, Maiato, H, and Italiano, J E
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- 2013
13. The roles of cohesin and CTCF for shaping the chromatin fiber: SW01.S1–5
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Wendt, K. S., Zuinl, J., Dixon, J. R., van der Reijden, M. I.J. A., Kolovos, P., Ye, Z., Brouwer, R. W.W., van de Corput, M. P.C., van IJcken, W. F.J., Grosveld, F. G., and Ren, B.
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- 2013
14. NARWHAL, a primary analysis pipeline for NGS data
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Brouwer, R. W. W., van den Hout, M. C. G. N., Grosveld, F. G., and van IJcken, W. F. J.
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- 2012
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15. Inflammatory conditions affect gene expression and function of human adipose tissue-derived mesenchymal stem cells
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Crop, M. J., Baan, C. C., Korevaar, S. S., IJzermans, J. N. M., Pescatori, M., Stubbs, A. P., Van IJcken, W. F. J., Dahlke, M. H., Eggenhofer, E., Weimar, W., and Hoogduijn, M. J.
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- 2010
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16. Circulating TP53 mutations are predictive and prognostic biomarkers in pancreatic cancer patients treated with FOLFIRINOX chemotherapy
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Van Der Sijde, F., Azmani, Z., Besselink, M., Bonsing, B., de Groot, J.W., Koerkamp, B. Groot, Haberkorn, B., Homs, M., van Ijcken, W., Janssen, Q., Lolkema, M., Luelmo, S., Mekenkamp, L., Mustafa, D., van Schaik, R., Wilmink, J., van Eijck, C., and Vietsch, E.
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- 2021
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17. A new function of ROD1 in nonsense-mediated mRNA decay
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Brazão, T.F., Demmers, J., van IJcken, W., Strouboulis, J., Fornerod, M., Romão, L., and Grosveld, F.G.
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- 2012
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18. Gene expression-based classification of non-small cell lung carcinomas and survival prediction
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Hou, J, Aerts, Joeri, Den Hamer, B, Van Ijcken, W, Den Bakker, M, Riegman, P, Van Der Leest, C, Van Der Spek, P, Foekens, Ja, Grosveld, F, Philipsen, S, and Physiology
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gene expression-base non-small lung carcinomas - Abstract
BACKGROUND: Current clinical therapy of non-small cell lung cancer depends on histo-pathological classification. This approach poorly predicts clinical outcome for individual patients. Gene expression profiling holds promise to improve clinical stratification, thus paving the way for individualized therapy. METHODOLOGY AND PRINCIPAL FINDINGS: A genome-wide gene expression analysis was performed on a cohort of 91 patients. We used 91 tumor- and 65 adjacent normal lung tissue samples. We defined sets of predictor genes (probe sets) with the expression profiles. The power of predictor genes was evaluated using an independent cohort of 96 non-small cell lung cancer- and 6 normal lung samples. We identified a tumor signature of 5 genes that aggregates the 156 tumor and normal samples into the expected groups. We also identified a histology signature of 75 genes, which classifies the samples in the major histological subtypes of non-small cell lung cancer. Correlation analysis identified 17 genes which showed thebest association with post-surgery survival time. This signature was used for stratification of all patients in two risk groups. Kaplan-Meier survival curves show that the two groups display a significant difference in post-surgery survival time (p = 5.6E-6). The performance of the signatures was validated using a patient cohort of similar size (Duke University, n = 96). Compared to previously published prognostic signatures for NSCLC, the 17 gene signature performed well on these two cohorts. CONCLUSIONS: The gene signatures identified are promising tools for histo-pathological classification of non-small cell lung cancer, and may improve the prediction of clinical outcome.
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- 2010
19. MiR-17-92 and miR-221/222 cluster members target KIT and ETV1 in human gastrointestinal stromal tumours.
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Gits, C M M, van Kuijk, P F, Jonkers, M B E, Boersma, A W M, van IJcken, W F, Wozniak, A, Sciot, R, Rutkowski, P, Schöffski, P, Taguchi, T, Mathijssen, R H J, Verweij, J, Sleijfer, S, Debiec-Rychter, M, and Wiemer, E A C
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GASTROINTESTINAL stromal tumors ,GENE expression ,CARCINOGENESIS ,CLUSTER analysis (Statistics) ,LUCIFERASES ,MICRORNA ,GENE targeting ,IMATINIB - Abstract
Background:Gastrointestinal stromal tumours (GIST) are characterised by high expression of KIT and ETV1, which cooperate in GIST oncogenesis. Our aim was to identify microRNAs that are deregulated in GIST, have a role in GIST pathogenesis, and could potentially be used as therapeutic tool.Methods:Differentially expressed microRNAs between primary GIST (n=50) and gastrointestinal leiomyosarcomas (GI-LMS, n=10) were determined using microarrays. Selected microRNA mimics were transfected into GIST-882 and GIST-T1 cell lines to study the effects of microRNA overexpression on GIST cells. Luciferase reporter assays were used to establish regulation of target genes by selected microRNAs.Results:MiR-17-92 and miR-221/222 cluster members were significantly (P<0.01) lower expressed in GIST vs GI-LMS and normal gastrointestinal control tissues. MiR-17/20a/222 overexpression in GIST cell lines severely inhibited cell proliferation, affected cell cycle progression, induced apoptosis and strongly downregulated protein and - to a lesser extent - mRNA levels of their predicted target genes KIT and ETV1. Luciferase reporter assays confirmed direct regulation of KIT and ETV1 by miR-222 and miR-17/20a, respectively.Conclusion:MicroRNAs that may have an essential role in GIST pathogenesis were identified, in particular miR-17/20a/222 that target KIT and ETV1. Delivering these microRNAs therapeutically could hold great potential for GIST management, especially in imatinib-resistant disease. [ABSTRACT FROM AUTHOR]
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- 2013
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20. Pandemic 2009 H1N1 Influenza Virus Causes Diffuse Alveolar Damage in Cynomolgus Macaques.
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Herfst, S., Van den Brand, J. M. A., Schrauwen, E. J. A., de Wit, E., Munster, V. J., van Amerongen, G., Linster, M., Zaaraoui, F., van Ijcken, W. F. J., Rimmelzwaan, G. F., Osterhaus, A. D. M. E., Fouchier, R. A. M., Andeweg, A. C., and Kuiken, T.
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INFLUENZA A virus, H1N1 subtype ,KRA ,MACAQUES ,INFLUENZA ,PNEUMONIA ,VIROLOGY ,PATHOLOGY ,ANIMAL experimentation - Abstract
The article discusses a study which examined the introduction of either the H1N1v virus or a seasonal human H1N1 influenza virus into cynomolgus macaques for the establishment of a nonhuman primate model of influenza pneumonia. It explains the methodology used for the study, such as virological, pathological, and microarray analyses. The result of the study showed that H1N1v virus affects the alveolar epithelial cells which ten causes diffuse alveolar damage in a nonhuman primate model.
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- 2010
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21. CITED2 and NCOR2 in anti-oestrogen resistance and progression of breast cancer.
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van Agthoven, T., Sieuwerts, A. M., Veldscholte, J., Meijer-van Gelder, M. E., Smid, M., Brinkman, A., den Dekker, A. T., Leroy, I. M., van IJcken, W. F. J., Sleijfer, S., Foekens, J. A., and Dorssers, L. C. J.
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ESTROGEN ,ANTI-estrogenic diet ,BREAST cancer treatment ,RETROVIRUS diseases ,MUTAGENESIS ,PROTEIN metabolism ,PROTEINS ,SURVIVAL ,REVERSE transcriptase polymerase chain reaction ,RESEARCH ,RESEARCH methodology ,ESTROGEN antagonists ,PROGNOSIS ,METASTASIS ,RETROSPECTIVE studies ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,GENE expression profiling ,TAMOXIFEN ,POLYMERASE chain reaction ,CELL lines ,BREAST tumors ,DRUG resistance in cancer cells ,MORSE Fall Scale ,PHARMACODYNAMICS - Abstract
Background: Endocrine therapies of breast cancer are effective but ultimately fail because of the development of treatment resistance. We have previously revealed several genes leading to tamoxifen resistance in vitro by retroviral insertion mutagenesis. To understand the manner in which these genes yield tamoxifen resistance, their effects on global gene expression were studied and those genes resulting in a distinct gene expression profile were further investigated for their clinical relevance.Methods: Gene expression profiles of 69 human breast cancer cell lines that were made tamoxifen resistant through retroviral insertion mutagenesis were obtained using oligonucleotide arrays and analysed with bioinformatic tools. mRNA levels of NCOR2 and CITED2 in oestrogen receptor-positive breast tumours were determined by quantitative RT-PCR. mRNA levels were evaluated for association with metastasis-free survival (MFS) in 620 patients with lymph node-negative primary breast cancer who did not receive systemic adjuvant therapy, and with clinical benefit in 296 patients receiving tamoxifen therapy for recurrent breast cancer.Results: mRNA expression profiles of most tamoxifen-resistant cell lines were strikingly similar, except for the subgroups of cell lines in which NCOR2 or CITED2 were targeted by the retrovirus. Both NCOR2 and CITED2 mRNA levels were associated with MFS, that is, tumour aggressiveness, independently of traditional prognostic factors. In addition, high CITED2 mRNA levels were predictive for a clinical benefit from first-line tamoxifen treatment in patients with advanced disease.Conclusions: Most retrovirally targeted genes yielding tamoxifen resistance in our cell lines do not impose a distinctive expression profile, suggesting that their causative role in cell growth may be accomplished by post-transcriptional processes. The associations of NCOR2 and CITED2 with outcome in oestrogen receptor-positive breast cancer patients underscore the clinical relevance of functional genetic screens to better understand disease progression, which may ultimately lead to the development of improved treatment options. [ABSTRACT FROM AUTHOR]- Published
- 2009
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22. Genome-wide DNA methylation profiling of non-small cell lung carcinomas
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Carvalho Rejane, Haberle Vanja, Hou Jun, van Gent Teus, Thongjuea Supat, van IJcken Wilfred, Kockx Christel, Brouwer Rutger, Rijkers Erikjan, Sieuwerts Anieta, Foekens John, van Vroonhoven Mirjam, Aerts Joachim, Grosveld Frank, Lenhard Boris, and Philipsen Sjaak
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DNA Methylation ,Epigenetics ,MethylCap ,Next generation sequencing ,Non-small cell lung Cancer ,Genetics ,QH426-470 - Abstract
Abstract Background Non-small cell lung carcinoma (NSCLC) is a complex malignancy that owing to its heterogeneity and poor prognosis poses many challenges to diagnosis, prognosis and patient treatment. DNA methylation is an important mechanism of epigenetic regulation involved in normal development and cancer. It is a very stable and specific modification and therefore in principle a very suitable marker for epigenetic phenotyping of tumors. Here we present a genome-wide DNA methylation analysis of NSCLC samples and paired lung tissues, where we combine MethylCap and next generation sequencing (MethylCap-seq) to provide comprehensive DNA methylation maps of the tumor and paired lung samples. The MethylCap-seq data were validated by bisulfite sequencing and methyl-specific polymerase chain reaction of selected regions. Results Analysis of the MethylCap-seq data revealed a strong positive correlation between replicate experiments and between paired tumor/lung samples. We identified 57 differentially methylated regions (DMRs) present in all NSCLC tumors analyzed by MethylCap-seq. While hypomethylated DMRs did not correlate to any particular functional category of genes, the hypermethylated DMRs were strongly associated with genes encoding transcriptional regulators. Furthermore, subtelomeric regions and satellite repeats were hypomethylated in the NSCLC samples. We also identified DMRs that were specific to two of the major subtypes of NSCLC, adenocarcinomas and squamous cell carcinomas. Conclusions Collectively, we provide a resource containing genome-wide DNA methylation maps of NSCLC and their paired lung tissues, and comprehensive lists of known and novel DMRs and associated genes in NSCLC.
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- 2012
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23. The male germ cell gene regulator CTCFL is functionally different from CTCF and binds CTCF-like consensus sites in a nucleosome composition-dependent manner
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Sleutels Frank, Soochit Widia, Bartkuhn Marek, Heath Helen, Dienstbach Sven, Bergmaier Philipp, Franke Vedran, Rosa-Garrido Manuel, van de Nobelen Suzanne, Caesar Lisa, van der Reijden Michael, Bryne Jan, van IJcken Wilfred, Grootegoed J, Delgado M, Lenhard Boris, Renkawitz Rainer, Grosveld Frank, and Galjart Niels
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CTCF ,CTCFL ,Gametogenesis ,Genome-wide binding ,Nucleosome ,Genetics ,QH426-470 - Abstract
Abstract Background CTCF is a highly conserved and essential zinc finger protein expressed in virtually all cell types. In conjunction with cohesin, it organizes chromatin into loops, thereby regulating gene expression and epigenetic events. The function of CTCFL or BORIS, the testis-specific paralog of CTCF, is less clear. Results Using immunohistochemistry on testis sections and fluorescence-based microscopy on intact live seminiferous tubules, we show that CTCFL is only transiently present during spermatogenesis, prior to the onset of meiosis, when the protein co-localizes in nuclei with ubiquitously expressed CTCF. CTCFL distribution overlaps completely with that of Stra8, a retinoic acid-inducible protein essential for the propagation of meiosis. We find that absence of CTCFL in mice causes sub-fertility because of a partially penetrant testicular atrophy. CTCFL deficiency affects the expression of a number of testis-specific genes, including Gal3st1 and Prss50. Combined, these data indicate that CTCFL has a unique role in spermatogenesis. Genome-wide RNA expression studies in ES cells expressing a V5- and GFP-tagged form of CTCFL show that genes that are downregulated in CTCFL-deficient testis are upregulated in ES cells. These data indicate that CTCFL is a male germ cell gene regulator. Furthermore, genome-wide DNA-binding analysis shows that CTCFL binds a consensus sequence that is very similar to that of CTCF. However, only ~3,700 out of the ~5,700 CTCFL- and ~31,000 CTCF-binding sites overlap. CTCFL binds promoters with loosely assembled nucleosomes, whereas CTCF favors consensus sites surrounded by phased nucleosomes. Finally, an ES cell-based rescue assay shows that CTCFL is functionally different from CTCF. Conclusions Our data suggest that nucleosome composition specifies the genome-wide binding of CTCFL and CTCF. We propose that the transient expression of CTCFL in spermatogonia and preleptotene spermatocytes serves to occupy a subset of promoters and maintain the expression of male germ cell genes.
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- 2012
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24. Cell-specific occupancy of an extended repertoire of CREM and CREB binding loci in male germ cells
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Sassone-Corsi Paolo, Jost Bernard, Van Ijcken Wilfred, Rijkers Erikjan, Legras Stephanie, Ye Tao, Krebs Arnaud, Choukrallah Mohamed-Amin, Martianov Igor, and Davidson Irwin
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Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background CREB and CREM are closely related factors that regulate transcription in response to various stress, metabolic and developmental signals. The CREMτ activator isoform is selectively expressed in haploid spermatids and plays an essential role in murine spermiogenesis. Results We have used chromatin immunoprecipitation coupled to sequencing (ChIP-seq) to map CREM and CREB target loci in round spermatids from adult mouse testis and spermatogonia derived GC1-spg cells respectively. We identify more than 9000 genomic loci most of which are cell-specifically occupied. Despite the fact that round spermatids correspond to a highly specialised differentiated state, our results show that they have a remarkably accessible chromatin environment as CREM occupies more than 6700 target loci corresponding not only to the promoters of genes selectively expressed in spermiogenesis, but also of genes involved in functions specific to other cell types. The expression of only a small subset of these target genes are affected in the round spermatids of CREM knockout animals. We also identify a set of intergenic binding loci some of which are associated with H3K4 trimethylation and elongating RNA polymerase II suggesting the existence of novel CREB and CREM regulated transcripts. Conclusions We demonstrate that CREM and CREB occupy a large number of promoters in highly cell specific manner. This is the first study of CREM target promoters directly in a physiologically relevant tissue in vivo and represents the most comprehensive experimental analysis of CREB/CREM regulatory potential to date.
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- 2010
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25. The ubiquitin-conjugating enzyme HR6B is required for maintenance of X chromosome silencing in mouse spermatocytes and spermatids
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van IJcken Wilfred FJ, Sun Zu-Wen, Ooms Marja, Sleddens-Linkels Esther, Hoogerbrugge Jos W, Wassenaar Evelyne, Mulugeta Achame Eskeatnaf, Grootegoed J Anton, and Baarends Willy M
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Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background The ubiquitin-conjugating enzyme HR6B is required for spermatogenesis in mouse. Loss of HR6B results in aberrant histone modification patterns on the trancriptionally silenced X and Y chromosomes (XY body) and on centromeric chromatin in meiotic prophase. We studied the relationship between these chromatin modifications and their effects on global gene expression patterns, in spermatocytes and spermatids. Results HR6B is enriched on the XY body and on centromeric regions in pachytene spermatocytes. Global gene expression analyses revealed that spermatid-specific single- and multicopy X-linked genes are prematurely expressed in Hr6b knockout spermatocytes. Very few other differences in gene expression were observed in these cells, except for upregulation of major satellite repeat transcription. In contrast, in Hr6b knockout spermatids, 7298 genes were differentially expressed; 65% of these genes was downregulated, but we observed a global upregulation of gene transcription from the X chromosome. In wild type spermatids, approximately 20% of the single-copy X-linked genes reach an average expression level that is similar to the average expression from autosomes. Conclusions Spermatids maintain an enrichment of repressive chromatin marks on the X chromosome, originating from meiotic prophase, but this does not interfere with transcription of the single-copy X-linked genes that are reactivated or specifically activated in spermatids. HR6B represses major satellite repeat transcription in spermatocytes, and functions in the maintenance of X chromosome silencing in spermatocytes and spermatids. It is discussed that these functions involve modification of chromatin structure, possibly including H2B ubiquitylation.
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- 2010
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26. FUNCTION OF HUMAN MESENCHYMAL STEM CELLS UNDER INFLAMMATORY CONDITIONS.
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Hoogduijn, M. J., Crop, M. J., Korevaar, S. S., Ijzermans, J. N., Pescatori, M., Stubbs, A. P., Van Ijcken, W. F., Eggenhofer, E., Dahlke, M. H., Weimar, W., and Baan, C.
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- 2010
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27. BACH2: A marker of DNA damage and ageing.
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Uittenboogaard, L.M., Payan-Gomez, C., Pothof, J., van IJcken, W., Mastroberardino, P.G., van der Pluijm, I., Hoeijmakers, J.H.J., and Tresini, M.
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DNA damage , *BIOMARKERS , *META-analysis , *AGING , *GENE expression , *REPORTER genes , *GENETIC transcription - Abstract
Highlights: [•] Meta-analysis identifies genes with conserved response to ageing and DNA damage. [•] Transcriptional regulator BACH2 is suppressed during ageing and in response to DNA damage. [•] Bach2 expression is a rapid and highly sensitive reporter of DNA damage. [•] Transcription blocking DNA lesions are directly responsible for Bach2 attenuation. [•] Bach2 overexpression is detrimental to cell survival. [Copyright &y& Elsevier]
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- 2013
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28. FOXA1 expression: regulated by EZH2 and associated with favorable outcome to tamoxifen in advanced breast cancer.
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Reijm, E. A., A. Helmijr, J. C., Soler, C. M. J., Beekman, R., Gerritse, F. L., Prager-van, der Smissen W. J. C., Ruigrok.-Ritstier, K., van IJcken, W. F. J., Stevens, M. G., Smid, M., Look, M. P., Meijer, M. E., Sieuwerts, A. M., Sleijfer, S., Foekens, J. A., Berns, E. M. J. J., and Jansen, M. P. H. M.
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HISTONE methyltransferases , *ESTROGEN receptors , *HISTONES , *TAMOXIFEN , *GENETIC transcription - Abstract
Background: Enhancer of Zeste Homolog 2 (EZH2) is a member of the polycomb complex 2 and serves as a histone methyltransferase. Through trimethylation of histone 3 of lysine 27, EZH2 regulates 'genome wide' gene transcription silencing. Downregulation of EZH2 is associated with increased expression of the estrogen receptor (ER) and favorable outcome to tamoxifen in metastatic breast cancer. The binding of ER to its target genes is enhanced by Forkhead Box A1 (FOXA1), a pioneer factor that binds to and opens chromatized DNA. The aim of this study is to investigate the potential association between EZH2 and FOXA1 and their relation with treatment outcome in patients with advanced breast cancer. Experimental design: EZH2 and FOXA1 mRNA levels were analysed using available gene expression profile-data of 344 primary breast cancer specimens of lymph-node-negative (LNN) patients and in 109 ER-positive (ER+) tumors of patients with metastatic disease treated with first-line tamoxifen. To functionally analyze EZH2, cell lines were generated with different knockdown-constructs for EZH2, followed by evaluation of mRNA and protein expression levels and chromatin immunoprecipitation (ChIP) experiments combined with qPCR and/or next generation sequencing (NGS; ChIPseq). Results: In the 344 LNN breast tumors, EZH2 was highly expressed in breast tumors of the basal subtype. In contrast, FOXA1 was hardly expressed in this subtype, but highly in the luminal A and B subtypes. FOXA1 was related to a prolonged time to progression (TTP) after tamoxifen (HR = 0.51 [0.35-0.74], P < 0.001) in 59 LNN patients with ER+ primary tumors and advanced disease. This positive association between FOXA1 and TTP could be confirmed in an independent set of 109 ER+ primary tumors of patients with metastatic disease treated with tamoxifen (HR = 0.56 [0.37-0.85] p = 0.006). We obtained 50-70% EZH2 knockdown in the breast cancer cell lines MCF7 (ER+/PR+/FOXA1+), SUM52PE (ER+/PR-/FOXA1+), and MM231 (ER-/PR-/FOXA1-). ChIP followed by qPCR demonstrated higher levels of H3K27 trimethylation at the ER-locus in the parental cell lines compared to the EZH2-knockdowns for MM231 and at the PR-locus for SUM52PE and MM231. ChIPseq evaluation in the EZH2 knockdown of MM231 identified 200 loci with a significant decrease in read numbers for H3K27me3 compared to the parental. Interestingly, amongst these 200 loci the FOXA1 -locus was identified. These results suggest FOXA1 as an EZH2-target since its expression was not seen in the parental MM231. Conclusion: High EZH2 and low FOXA1 mRNA levels are associated with poor clinical outcome for tamoxifen therapy of advanced breast cancer. Functional studies indicate that EZH2 might regulate the expression of FOXA1. These results suggest that EZH2 and/or FOXA1 could be used as a predictive marker to identify patients at risk for tamoxifen therapy failure and possibly as a target for therapy. [ABSTRACT FROM AUTHOR]
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- 2012
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29. Mutation Analysis of Pancreatic Juice and Plasma for the Detection of Pancreatic Cancer.
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Levink IJM, Jansen MPHM, Azmani Z, van IJcken W, van Marion R, Peppelenbosch MP, Cahen DL, Fuhler GM, and Bruno MJ
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- Humans, Female, Child, Male, Pancreatic Juice, Prospective Studies, Proto-Oncogene Proteins p21(ras) genetics, Biocompatible Materials, Pancreatic Neoplasms, Pancreatic Intraductal Neoplasms, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms genetics, Cell-Free Nucleic Acids genetics
- Abstract
Molecular profiling may enable earlier detection of pancreatic cancer (PC) in high-risk individuals undergoing surveillance and allow for personalization of treatment. We hypothesized that the detection rate of DNA mutations is higher in pancreatic juice (PJ) than in plasma due to its closer contact with the pancreatic ductal system, from which pancreatic cancer cells originate, and higher overall cell-free DNA (cfDNA) concentrations. In this study, we included patients with pathology-proven PC or intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia (HGD) from two prospective clinical trials (KRASPanc and PACYFIC) for whom both PJ and plasma were available. We performed next-generation sequencing on PJ, plasma, and tissue samples and described the presence (and concordance) of mutations in these biomaterials. This study included 26 patients (25 PC and 1 IPMN with HGD), of which 7 were women (27%), with a median age of 71 years (IQR 12) and a median BMI of 23 kg/m
2 (IQR 4). Ten patients with PC (40%) were (borderline) resectable at baseline. Tissue was available from six patients (resection n = 5, biopsy n = 1). A median volume of 2.9 mL plasma (IQR 1.0 mL) and 0.7 mL PJ (IQR 0.1 mL, p < 0.001) was used for DNA isolation. PJ had a higher median cfDNA concentration (2.6 ng/μL (IQR 4.2)) than plasma (0.29 ng/μL (IQR 0.40)). A total of 41 unique somatic mutations were detected: 24 mutations in plasma (2 KRAS , 15 TP53 , 2 SMAD4 , 3 CDKN2A 1 CTNNB1 , and 1 PIK3CA ), 19 in PJ (3 KRAS , 15 TP53 , and 1 SMAD4 ), and 8 in tissue (2 KRAS , 2 CDKN2A , and 4 TP53 ). The mutation detection rate (and the concordance with tissue) did not differ between plasma and PJ. In conclusion, while the concentration of cfDNA was indeed higher in PJ than in plasma, the mutation detection rate was not different. A few cancer-associated genetic variants were detected in both biomaterials. Further research is needed to increase the detection rate and assess the performance and suitability of plasma and PJ for PC (early) detection.- Published
- 2023
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30. PD-L1 checkpoint blockade promotes regulatory T cell activity that underlies therapy resistance.
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van Gulijk M, van Krimpen A, Schetters S, Eterman M, van Elsas M, Mankor J, Klaase L, de Bruijn M, van Nimwegen M, van Tienhoven T, van Ijcken W, Boon L, van der Schoot J, Verdoes M, Scheeren F, van der Burg SH, Lambrecht BN, Stadhouders R, Dammeijer F, Aerts J, and van Hall T
- Subjects
- Humans, Mice, Animals, T-Lymphocytes, Regulatory, B7-H1 Antigen, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Skin Neoplasms
- Abstract
Despite the clinical success of immune checkpoint blockade (ICB), in certain cancer types, most patients with cancer do not respond well. Furthermore, in patients for whom ICB is initially successful, this is often short-lived because of the development of resistance to ICB. The mechanisms underlying primary or secondary ICB resistance are incompletely understood. Here, we identified preferential activation and enhanced suppressive capacity of regulatory T cells (T
reg cells) in αPD-L1 therapy-resistant solid tumor-bearing mice. Treg cell depletion reversed resistance to αPD-L1 with concomitant expansion of effector T cells. Moreover, we found that tumor-infiltrating Treg cells in human patients with skin cancer, and in patients with non-small cell lung cancer, up-regulated a suppressive transcriptional gene program after ICB treatment, which correlated with lack of treatment response. αPD-1/PD-L1-induced PD-1+ Treg cell activation was also seen in peripheral blood of patients with lung cancer and mesothelioma, especially in nonresponders. Together, these data reveal that treatment with αPD-1 and αPD-L1 unleashes the immunosuppressive role of Treg cells, resulting in therapy resistance, suggesting that Treg cell targeting is an important adjunct strategy to enhance therapeutic efficacy.- Published
- 2023
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31. Bio-distribution and longevity of mesenchymal stromal cell derived membrane particles.
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Vos J, Tejeda-Mora H, Merino A, Wu L, Woud WW, Demmers JAA, van IJcken WFJ, Reinders MEJ, and Hoogduijn MJ
- Subjects
- Animals, Humans, Immunomodulation, Liver, Mice, Extracellular Vesicles metabolism, Mesenchymal Stem Cells metabolism
- Abstract
Vesicle-based medicines hold great promise for therapy development but essential knowledge on the bio-distribution and longevity of vesicles after administration is lacking. We generated vesicles from the membranes of human mesenchymal stromal cells (MSC) and we demonstrated earlier that these so-called membrane particles (MP) mediate immunomodulatory and regenerative responses in target cells. In the present study we examined the bio-distribution and longevity of MP after intravenous administration in mice. While most vesicle tracking methods are based on imaging techniques, which require labeling of vesicles and can only detect dense accumulations of vesicles, we used proteomics analysis to detect the presence of MP-derived proteins in multiple organs and tissues. MP proteins were mainly present in plasma and leukocytes at 1 h after injection, indicating that MP - in contrast to whole MSC - do not accumulate in the lungs upon first passage but remain in circulation. After 24 h, MP proteins were still present in plasma but were most abundant in the liver. RNA sequencing of livers demonstrated that MP impact liver function and in particular induce metabolic pathways. These data provide a clear view of the bio-distribution and longevity of MP, which is likely extrapolatable to other types of vesicles, and demonstrate that MP circulate for up to 24 h and may be a tool for targeting the liver., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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32. A kinase inhibitor screen reveals MEK1/2 as a novel therapeutic target to antagonize IGF1R-mediated antiestrogen resistance in ERα-positive luminal breast cancer.
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Wester L, Venneker S, Hazenoot M, Pont C, Koedoot E, Timmermans AM, Martens JWM, Jansen MPHM, Kockx CEM, van IJcken WFJ, Meerman JHN, Zhang Y, and van de Water B
- Subjects
- Anaplastic Lymphoma Kinase, Benzamides, Cell Line, Tumor, Diphenylamine analogs & derivatives, Drug Resistance, Neoplasm, ErbB Receptors, Estrogen Antagonists pharmacology, Estrogen Receptor alpha metabolism, Female, Humans, Insulin-Like Growth Factor I, Mitogen-Activated Protein Kinase Kinases, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Receptor, IGF Type 1, Tamoxifen pharmacology, Tamoxifen therapeutic use, Breast Neoplasms metabolism, Estrogen Receptor Modulators pharmacology, Estrogen Receptor Modulators therapeutic use
- Abstract
Antiestrogen resistance of breast cancer has been related to enhanced growth factor receptor expression and activation. We have previously shown that ectopic expression and subsequent activation of the insulin-like growth factor-1 receptor (IGF1R) or the epidermal growth factor receptor (EGFR) in MCF7 or T47D breast cancer cells results in antiestrogen resistance. In order to identify novel therapeutic targets to prevent this antiestrogen resistance, we performed kinase inhibitor screens with 273 different inhibitors in MCF7 cells overexpressing IGF1R or EGFR. Kinase inhibitors that antagonized antiestrogen resistance but are not directly involved in IGF1R or EGFR signaling were prioritized for further analyses. Various ALK (anaplastic lymphoma receptor tyrosine kinase) inhibitors inhibited cell proliferation in IGF1R expressing cells under normal and antiestrogen resistance conditions by preventing IGF1R activation and subsequent downstream signaling; the ALK inhibitors did not affect EGFR signaling. On the other hand, MEK (mitogen-activated protein kinase kinase)1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK-733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. RNAseq analysis revealed that MEK inhibitors PD0325901 and selumetinib drastically altered cell cycle progression and cell migration networks under IGF1R signaling-mediated antiestrogen resistance. In a group of 219 patients with metastasized ER + breast cancer, strong pMEK staining showed a significant correlation with no clinical benefit of first-line tamoxifen treatment. We propose a critical role for MEK activation in IGF1R signaling-mediated antiestrogen resistance and anticipate that dual-targeted therapy with a MEK inhibitor and antiestrogen could improve treatment outcome., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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33. Selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir.
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Rao S, Lungu C, Crespo R, Steijaert TH, Gorska A, Palstra RJ, Prins HAB, van Ijcken W, Mueller YM, van Kampen JJA, Verbon A, Katsikis PD, Boucher CAB, Rokx C, Gruters RA, and Mahmoudi T
- Subjects
- Anti-Retroviral Agents pharmacology, Apoptosis genetics, Azepines chemistry, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes virology, Cell Death drug effects, Cell Death genetics, Cell Survival drug effects, Cell Survival genetics, DEAD-box RNA Helicases antagonists & inhibitors, DEAD-box RNA Helicases chemistry, Enzyme Inhibitors pharmacology, HIV Infections genetics, HIV Infections metabolism, HIV Infections virology, HIV-1 drug effects, HIV-1 genetics, Humans, Imidazoles chemistry, In Situ Hybridization, Fluorescence, Interferon Regulatory Factor-3 metabolism, Interferon-beta metabolism, Jurkat Cells, Molecular Docking Simulation, RNA, Viral metabolism, Single-Cell Analysis, Survivin metabolism, Virus Activation drug effects, Virus Replication genetics, Apoptosis drug effects, Azepines pharmacology, CD4-Positive T-Lymphocytes drug effects, DEAD-box RNA Helicases metabolism, HIV Infections immunology, HIV-1 metabolism, Imidazoles pharmacology, Virus Latency drug effects, Virus Replication drug effects
- Abstract
An innovative approach to eliminate HIV-1-infected cells emerging out of latency, the major hurdle to HIV-1 cure, is to pharmacologically reactivate viral expression and concomitantly trigger intracellular pro-apoptotic pathways in order to selectively induce cell death (ICD) of infected cells, without reliance on the extracellular immune system. In this work, we demonstrate the effect of DDX3 inhibitors on selectively inducing cell death in latent HIV-1-infected cell lines, primary CD4+ T cells and in CD4+ T cells from cART-suppressed people living with HIV-1 (PLWHIV). We used single-cell FISH-Flow technology to characterise the contribution of viral RNA to inducing cell death. The pharmacological targeting of DDX3 induced HIV-1 RNA expression, resulting in phosphorylation of IRF3 and upregulation of IFNβ. DDX3 inhibition also resulted in the downregulation of BIRC5, critical to cell survival during HIV-1 infection, and selectively induced apoptosis in viral RNA-expressing CD4+ T cells but not bystander cells. DDX3 inhibitor treatment of CD4+ T cells from PLWHIV resulted in an approximately 50% reduction of the inducible latent HIV-1 reservoir by quantitation of HIV-1 RNA, by FISH-Flow, RT-qPCR and TILDA. This study provides proof of concept for pharmacological reversal of latency coupled to induction of apoptosis towards the elimination of the inducible reservoir.
- Published
- 2021
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34. Hemolysis in the spleen drives erythrocyte turnover.
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Klei TRL, Dalimot J, Nota B, Veldthuis M, Mul FPJ, Rademakers T, Hoogenboezem M, Nagelkerke SQ, van IJcken WFJ, Oole E, Svendsen P, Moestrup SK, van Alphen FPJ, Meijer AB, Kuijpers TW, van Zwieten R, and van Bruggen R
- Subjects
- Animals, Biomarkers, Erythrocyte Aging drug effects, Erythrocyte Deformability, Erythrocyte Membrane, Erythrocyte Transfusion, Erythrocytes drug effects, Female, Gene Expression Profiling, Histocytochemistry, Humans, Immunophenotyping, Laminin pharmacology, Macrophages metabolism, Mice, Phagocytosis, Erythrocytes metabolism, Hemolysis, Spleen metabolism, Spleen physiopathology
- Abstract
Red pulp macrophages (RPMs) of the spleen mediate turnover of billions of senescent erythrocytes per day. However, the molecular mechanisms involved in sequestration of senescent erythrocytes, their recognition, and their subsequent degradation by RPMs remain unclear. In this study, we provide evidence that the splenic environment is of substantial importance in facilitating erythrocyte turnover through induction of hemolysis. Upon isolating human spleen RPMs, we noted a substantial lack of macrophages that were in the process of phagocytosing intact erythrocytes. Detailed characterization of erythrocyte and macrophage subpopulations from human spleen tissue led to the identification of erythrocytes that are devoid of hemoglobin, so-called erythrocyte ghosts. By using in vivo imaging and transfusion experiments, we further confirmed that senescent erythrocytes that are retained in the spleen are subject to hemolysis. In addition, we showed that erythrocyte adhesion molecules, which are specifically activated on aged erythrocytes, cause senescent erythrocytes to interact with extracellular matrix proteins that are exposed within the splenic architecture. Such adhesion molecule-driven retention of senescent erythrocytes under low shear conditions was found to result in steady shrinkage of the cell and ultimately resulted in hemolysis. In contrast to intact senescent erythrocytes, the remnant erythrocyte ghost shells were prone to recognition and breakdown by RPMs. These data identify hemolysis as a key event in the turnover of senescent erythrocytes, which alters our current understanding of how erythrocyte degradation is regulated., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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35. Gliotoxin, identified from a screen of fungal metabolites, disrupts 7SK snRNP, releases P-TEFb, and reverses HIV-1 latency.
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Stoszko M, Al-Hatmi AMS, Skriba A, Roling M, Ne E, Crespo R, Mueller YM, Najafzadeh MJ, Kang J, Ptackova R, LeMasters E, Biswas P, Bertoldi A, Kan TW, de Crignis E, Sulc M, Lebbink JHG, Rokx C, Verbon A, van Ijcken W, Katsikis PD, Palstra RJ, Havlicek V, de Hoog S, and Mahmoudi T
- Subjects
- HeLa Cells, Humans, Positive Transcriptional Elongation Factor B genetics, Positive Transcriptional Elongation Factor B metabolism, RNA-Binding Proteins metabolism, Ribonucleoproteins, Ribonucleoproteins, Small Nuclear chemistry, Transcription Factors metabolism, Gliotoxin metabolism, HIV Infections drug therapy, HIV-1 metabolism
- Abstract
A leading pharmacological strategy toward HIV cure requires "shock" or activation of HIV gene expression in latently infected cells with latency reversal agents (LRAs) followed by their subsequent clearance. In a screen for novel LRAs, we used fungal secondary metabolites as a source of bioactive molecules. Using orthogonal mass spectrometry (MS) coupled to latency reversal bioassays, we identified gliotoxin (GTX) as a novel LRA. GTX significantly induced HIV-1 gene expression in latent ex vivo infected primary cells and in CD4
+ T cells from all aviremic HIV-1+ participants. RNA sequencing identified 7SK RNA, the scaffold of the positive transcription elongation factor b (P-TEFb) inhibitory 7SK small nuclear ribonucleoprotein (snRNP) complex, to be significantly reduced upon GTX treatment of CD4+ T cells. GTX directly disrupted 7SK snRNP by targeting La-related protein 7 (LARP7), releasing active P-TEFb, which phosphorylated RNA polymerase II (Pol II) C-terminal domain (CTD), inducing HIV transcription., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)- Published
- 2020
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36. Nimbus: a design-driven analyses suite for amplicon-based NGS data.
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Brouwer RWW, van den Hout MCGN, Kockx CEM, Brosens E, Eussen B, de Klein A, Sleutels F, and van IJcken WFJ
- Subjects
- Female, Humans, Male, Sequence Alignment, High-Throughput Nucleotide Sequencing methods, Polymorphism, Single Nucleotide, Sequence Analysis, DNA methods, Software
- Abstract
Motivation: PCR-based DNA enrichment followed by massively parallel sequencing is a straightforward and cost effective method to sequence genes up to high depth. The full potential of amplicon-based sequencing assays is currently not achieved as analysis methods do not take into account the source amplicons of the detected variants. Tracking the source amplicons has the potential to identify systematic biases, enhance variant calling and improve the designs of future assays., Results: We present Nimbus, a software suite for the analysis of amplicon-based sequencing data. Nimbus includes tools for data pre-processing, alignment, single nucleotide polymorphism (SNP), insertion and deletion calling, quality control and visualization. Nimbus can detect SNPs in its alignment seeds and reduces alignment issues by the usage of decoy amplicons. Tracking the amplicons throughout analysis allows easy and fast design optimization by amplicon performance comparison. It enables detection of probable false positive variants present in a single amplicon from real variants present in multiple amplicons and provides multiple sample visualization. Nimbus was tested using HaloPlex Exome datasets and outperforms other callers for low-frequency variants. The variants called by Nimbus were highly concordant between twin samples and SNP-arrays. The Nimbus suite provides an end-to-end solution for variant calling, design optimization and visualization of amplicon-derived next-generation sequencing datasets., Availability and Implementation: https://github.com/erasmus-center-for-biomics/Nimbus., Supplementary Information: Supplementary data are available at Bioinformatics online.
- Published
- 2018
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37. A rare missense variant in RCL1 segregates with depression in extended families.
- Author
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Amin N, de Vrij FMS, Baghdadi M, Brouwer RWW, van Rooij JGJ, Jovanova O, Uitterlinden AG, Hofman A, Janssen HLA, Darwish Murad S, Kraaij R, Stedehouder J, van den Hout MCGN, Kros JM, van IJcken WFJ, Tiemeier H, Kushner SA, and van Duijn CM
- Subjects
- Adult, Aged, Alleles, Animals, Exome, Exons, Family, Female, Gene Frequency genetics, Genetic Linkage genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study, Haplotypes genetics, Humans, Male, Mice, Middle Aged, Mutation, Pedigree, Polymorphism, Single Nucleotide genetics, Risk Factors, Exome Sequencing, Depression genetics, Depressive Disorder genetics
- Abstract
Depression is the most prevalent psychiatric disorder with a complex and elusive etiology that is moderately heritable. Identification of genes would greatly facilitate the elucidation of the biological mechanisms underlying depression, however, its complex etiology has proved to be a major bottleneck in the identification of its genetic risk factors, especially in genome-wide association-like studies. In this study, we exploit the properties of a genetic isolate and its family-based structure to explore whether relatively rare exonic variants influence the burden of depressive symptoms in families. Using a multistep approach involving linkage and haplotype analyses followed by exome sequencing in the Erasmus Rucphen Family (ERF) study, we identified a rare (minor allele frequency (MAF)=1%) missense c.1114C>T mutation (rs115482041) in the RCL1 gene segregating with depression across multiple generations. Rs115482041 showed significant association with depressive symptoms (N=2393, β
T-allele =2.33, P-value=1 × 10-4 ) and explained 2.9% of the estimated genetic variance of depressive symptoms (22%) in ERF. Despite being twice as rare (MAF<0.5%), c.1114C>T showed similar effect and significant association with depressive symptoms in samples from the independent population-based Rotterdam study (N=1604, βT-allele =3.60, P-value=3 × 10-2 ). A comparison of RCL1 expression in human and mouse brain revealed a striking co-localization of RCL1 with the layer 1 interlaminar subclass of astrocytes found exclusively in higher-order primates. Our findings identify RCL1 as a novel candidate gene for depression and offer insights into mechanisms through which RCL1 may be relevant for depression.- Published
- 2018
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38. Analysis of Mouse Brain Transcriptome After Experimental Duvenhage Virus Infection Shows Activation of Innate Immune Response and Pyroptotic Cell Death Pathway.
- Author
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Koraka P, Martina BEE, van den Ham HJ, Zaaraoui-Boutahar F, van IJcken W, Roose J, van Amerongen G, Andeweg A, and Osterhaus ADME
- Abstract
Rabies is an important neglected disease, characterized by invariably fatal encephalitis. Several studies focus on understanding the pathogenic mechanisms of the prototype lyssavirus rabies virus (RABV) infection, and little is known about the pathogenesis of rabies caused by other lyssaviruses. We sought to characterize the host response to Duvenhage virus infection and compare it with responses observed during RABV infection by gene expression profiling of brains of mice with the respective infections. We found in both infections differentially expressed genes leading to increased expression of type I interferons (IFNs), chemokines, and proinflammatory cytokines. In addition several genes of the IFN signaling pathway are up-regulated, indicating a strong antiviral response and activation of the negative feedback mechanism to limit type I IFN responses. Furthermore we provide evidence that in the absence of significant neuronal apoptotic death, cell death of neurons is mediated via the pyroptotic pathway in both infections. Taken together, we have identified several genes and/or pathways for both infections that could be used to explore novel approaches for intervention strategies against rabies.
- Published
- 2018
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39. Allele-specific long-distance regulation dictates IL-32 isoform switching and mediates susceptibility to HIV-1.
- Author
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Palstra RJ, de Crignis E, Röling MD, van Staveren T, Kan TW, van Ijcken W, Mueller YM, Katsikis PD, and Mahmoudi T
- Subjects
- CD4-Positive T-Lymphocytes immunology, Cytokines metabolism, DNA genetics, Deoxyribonuclease I metabolism, Enhancer Elements, Genetic genetics, HEK293 Cells, HIV Infections genetics, HIV Infections immunology, Haplotypes genetics, Humans, Inflammation pathology, Inflammation Mediators metabolism, Interleukins metabolism, Jurkat Cells, Polymorphism, Single Nucleotide genetics, Protein Isoforms genetics, Protein Isoforms metabolism, Alleles, Genetic Predisposition to Disease, HIV-1 physiology, Interleukins genetics
- Abstract
We integrated data obtained from HIV-1 genome-wide association studies with T cell-derived epigenome data and found that the noncoding intergenic variant rs4349147, which is statistically associated with HIV-1 acquisition, is located in a CD4
+ T cell-specific deoxyribonuclease I hypersensitive region, suggesting regulatory potential for this variant. Deletion of the rs4349147 element in Jurkat cells strongly reduced expression of interleukin-32 (IL-32), approximately 10-kb upstream, and chromosome conformation capture assays identified a chromatin loop between rs4349147 and the IL-32 promoter validating its function as a long-distance enhancer. We generated single rs4349147-A or rs4349147-G allele clones and demonstrated that IL-32 enhancer activity and interaction with the IL-32 promoter are strongly allele dependent; rs4349147 -/A cells display reduced IL-32 expression and altered chromatin conformation as compared to rs4349147 G/- cells. Moreover, RNA sequencing demonstrated that rs4349147 G/- cells express a lower relative ratio of IL-32α to non-α isoforms than rs4349147 -/A cells and display increased expression of lymphocyte activation factors rendering them more prone to infection with HIV-1. In agreement, in primary CD4+ T cells, both treatment with recombinant IL-32γ (rIL-32γ) but not rIL-32α, and exogenous lentiviral overexpression of IL-32γ or IL-32β but not IL-32α resulted in a proinflammatory T cell cytokine environment concomitant with increased susceptibility to HIV infection. Our data demonstrate that rs4349147-G promotes transcription of non-IL-32α isoforms, generating a proinflammatory environment more conducive to HIV infection. This study provides a mechanistic link between a HIV-associated noncoding DNA variant and the expression of different IL-32 isoforms that display discrete anti-HIV properties.- Published
- 2018
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40. Sensitive detection of mitochondrial DNA variants for analysis of mitochondrial DNA-enriched extracts from frozen tumor tissue.
- Author
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Weerts MJA, Timmermans EC, Vossen RHAM, van Strijp D, Van den Hout-van Vroonhoven MCGN, van IJcken WFJ, van der Zaag PJ, Anvar SY, Sleijfer S, and Martens JWM
- Subjects
- Cell Line, Tumor, Female, Freezing, Humans, Mass Spectrometry, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Sensitivity and Specificity, Sequence Analysis, DNA, Breast Neoplasms pathology, DNA, Mitochondrial genetics, DNA, Mitochondrial isolation & purification, Pathology, Molecular methods, Specimen Handling methods
- Abstract
Large variation exists in mitochondrial DNA (mtDNA) not only between but also within individuals. Also in human cancer, tumor-specific mtDNA variation exists. In this work, we describe the comparison of four methods to extract mtDNA as pure as possible from frozen tumor tissue. Also, three state-of-the-art methods for sensitive detection of mtDNA variants were evaluated. The main aim was to develop a procedure to detect low-frequent single-nucleotide mtDNA-specific variants in frozen tumor tissue. We show that of the methods evaluated, DNA extracted from cytosol fractions following exonuclease treatment results in highest mtDNA yield and purity from frozen tumor tissue (270-fold mtDNA enrichment). Next, we demonstrate the sensitivity of detection of low-frequent single-nucleotide mtDNA variants (≤1% allele frequency) in breast cancer cell lines MDA-MB-231 and MCF-7 by single-molecule real-time (SMRT) sequencing, UltraSEEK chemistry based mass spectrometry, and digital PCR. We also show de novo detection and allelic phasing of variants by SMRT sequencing. We conclude that our sensitive procedure to detect low-frequent single-nucleotide mtDNA variants from frozen tumor tissue is based on extraction of DNA from cytosol fractions followed by exonuclease treatment to obtain high mtDNA purity, and subsequent SMRT sequencing for (de novo) detection and allelic phasing of variants.
- Published
- 2018
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41. Genome-wide DNA methylation profiling using the methylation-dependent restriction enzyme LpnPI.
- Author
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Boers R, Boers J, de Hoon B, Kockx C, Ozgur Z, Molijn A, van IJcken W, Laven J, and Gribnau J
- Subjects
- Female, Humans, Chromosomes, Human, X chemistry, Chromosomes, Human, X genetics, Chromosomes, Human, X metabolism, CpG Islands, DNA Methylation physiology, Deoxyribonuclease I chemistry, Epigenesis, Genetic, Genome-Wide Association Study, X Chromosome Inactivation
- Abstract
DNA methylation is a well-known epigenetic modification that plays a crucial role in gene regulation, but genome-wide analysis of DNA methylation remains technically challenging and costly. DNA methylation-dependent restriction enzymes can be used to restrict CpG methylation analysis to methylated regions of the genome only, which significantly reduces the required sequencing depth and simplifies subsequent bioinformatics analysis. Unfortunately, this approach has been hampered by complete digestion of DNA in CpG methylation-dense regions, resulting in fragments that are too small for accurate mapping. Here, we show that the activity of DNA methylation-dependent enzyme, LpnPI, is blocked by a fragment size smaller than 32 bp. This unique property prevents complete digestion of methylation-dense DNA and allows accurate genome-wide analysis of CpG methylation at single-nucleotide resolution. Methylated DNA sequencing (MeD-seq) of LpnPI digested fragments revealed highly reproducible genome-wide CpG methylation profiles for >50% of all potentially methylated CpGs, at a sequencing depth less than one-tenth required for whole-genome bisulfite sequencing (WGBS). MeD-seq identified a high number of patient and tissue-specific differential methylated regions (DMRs) and revealed that patient-specific DMRs observed in both blood and buccal samples predict DNA methylation in other tissues and organs. We also observed highly variable DNA methylation at gene promoters on the inactive X Chromosome, indicating tissue-specific and interpatient-specific escape of X Chromosome inactivation. These findings highlight the potential of MeD-seq for high-throughput epigenetic profiling., (© 2018 Boers et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2018
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42. Cell lines generated from a chronic lymphocytic leukemia mouse model exhibit constitutive Btk and Akt signaling.
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Singh SP, Pillai SY, de Bruijn MJW, Stadhouders R, Corneth OBJ, van den Ham HJ, Muggen A, van IJcken W, Slinger E, Kuil A, Spaargaren M, Kater AP, Langerak AW, and Hendriks RW
- Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature CD5
+ B cells in blood. Spontaneous apoptosis of CLL cells in vitro has hampered in-depth investigation of CLL pathogenesis. Here we describe the generation of three monoclonal mouse cell lines, EMC2, EMC4 and EMC6, from the IgH.TEμ CLL mouse model based on sporadic expression of SV40 large T antigen. The cell lines exhibit a stable CD5+ CD43+ IgM+ CD19+ CLL phenotype in culture and can be adoptively transferred into Rag1-/- mice. RNA-seq analysis revealed only minor differences between the cell lines and their primary tumors and suggested that NF-κB and mTOR signaling pathways were involved in cell line outgrowth. In vitro survival and proliferation was dependent on constitutive phosphorylation of Bruton's tyrosine kinase (Btk) at Y551/Y223, and Akt(S473). Treatment of the cell lines with small molecule inhibitors specific for Btk (ibrutinib) or PI3K (idelalisib), which is upstream of Akt, resulted in reduced viability, proliferation and fibronectin-dependent cell adhesion. Treatment of cell line-engrafted Rag1-/- mice with ibrutinib was associated with transient lymphocytosis, reduced splenomegaly and increased overall survival. Thus, by generating stable cell lines we established a novel platform for in vitro and in vivo investigation of CLL signal transduction and treatment modalities., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.- Published
- 2017
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43. An interaction network of mental disorder proteins in neural stem cells.
- Author
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Moen MJ, Adams HH, Brandsma JH, Dekkers DH, Akinci U, Karkampouna S, Quevedo M, Kockx CE, Ozgür Z, van IJcken WF, Demmers J, and Poot RA
- Subjects
- Autism Spectrum Disorder genetics, Female, Gene Expression Regulation genetics, Genetic Predisposition to Disease genetics, Genetic Predisposition to Disease psychology, Genome, High-Throughput Nucleotide Sequencing methods, Humans, Intellectual Disability genetics, Male, Mutation, Schizophrenia genetics, Gene Regulatory Networks genetics, Neural Stem Cells metabolism, Psychotic Disorders genetics
- Abstract
Mental disorders (MDs) such as intellectual disability (ID), autism spectrum disorders (ASD) and schizophrenia have a strong genetic component. Recently, many gene mutations associated with ID, ASD or schizophrenia have been identified by high-throughput sequencing. A substantial fraction of these mutations are in genes encoding transcriptional regulators. Transcriptional regulators associated with different MDs but acting in the same gene regulatory network provide information on the molecular relation between MDs. Physical interaction between transcriptional regulators is a strong predictor for their cooperation in gene regulation. Here, we biochemically purified transcriptional regulators from neural stem cells, identified their interaction partners by mass spectrometry and assembled a protein interaction network containing 206 proteins, including 68 proteins mutated in MD patients and 52 proteins significantly lacking coding variation in humans. Our network shows molecular connections between established MD proteins and provides a discovery tool for novel MD genes. Network proteins preferentially co-localize on the genome and cooperate in disease-relevant gene regulation. Our results suggest that the observed transcriptional regulators associated with ID, ASD or schizophrenia are part of a transcriptional network in neural stem cells. We find that more severe mutations in network proteins are associated with MDs that include lower intelligence quotient (IQ), suggesting that the level of disruption of a shared transcriptional network correlates with cognitive dysfunction.
- Published
- 2017
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44. Exploiting native forces to capture chromosome conformation in mammalian cell nuclei.
- Author
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Brant L, Georgomanolis T, Nikolic M, Brackley CA, Kolovos P, van Ijcken W, Grosveld FG, Marenduzzo D, and Papantonis A
- Subjects
- Animals, High-Throughput Nucleotide Sequencing methods, Human Umbilical Vein Endothelial Cells, Humans, Interphase, K562 Cells, Mammals genetics, Models, Genetic, Nucleic Acid Conformation, Oligonucleotide Array Sequence Analysis, Sequence Analysis, DNA methods, Cell Nucleus genetics, Chromosomes, Human chemistry, Chromosomes, Human genetics
- Abstract
Mammalian interphase chromosomes fold into a multitude of loops to fit the confines of cell nuclei, and looping is tightly linked to regulated function. Chromosome conformation capture (3C) technology has significantly advanced our understanding of this structure-to-function relationship. However, all 3C-based methods rely on chemical cross-linking to stabilize spatial interactions. This step remains a "black box" as regards the biases it may introduce, and some discrepancies between microscopy and 3C studies have now been reported. To address these concerns, we developed "i3C", a novel approach for capturing spatial interactions without a need for cross-linking. We apply i3C to intact nuclei of living cells and exploit native forces that stabilize chromatin folding. Using different cell types and loci, computational modeling, and a methylation-based orthogonal validation method, "TALE-iD", we show that native interactions resemble cross-linked ones, but display improved signal-to-noise ratios and are more focal on regulatory elements and CTCF sites, while strictly abiding to topologically associating domain restrictions., (© 2016 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2016
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45. BMP and Hedgehog Regulate Distinct AGM Hematopoietic Stem Cells Ex Vivo.
- Author
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Crisan M, Solaimani Kartalaei P, Neagu A, Karkanpouna S, Yamada-Inagawa T, Purini C, Vink CS, van der Linden R, van Ijcken W, Chuva de Sousa Lopes SM, Monteiro R, Mummery C, and Dzierzak E
- Subjects
- Animals, Endothelial Cells cytology, Endothelial Cells metabolism, Hematopoietic Stem Cells metabolism, Mice, Mice, Inbred C57BL, Signal Transduction, Smad Proteins metabolism, Vascular Endothelial Growth Factor A metabolism, Bone Morphogenetic Protein 4 metabolism, Hedgehog Proteins metabolism, Hematopoiesis, Hematopoietic Stem Cells cytology
- Abstract
Hematopoietic stem cells (HSC), the self-renewing cells of the adult blood differentiation hierarchy, are generated during embryonic stages. The first HSCs are produced in the aorta-gonad-mesonephros (AGM) region of the embryo through endothelial to a hematopoietic transition. BMP4 and Hedgehog affect their production and expansion, but it is unknown whether they act to affect the same HSCs. In this study using the BRE GFP reporter mouse strain that identifies BMP/Smad-activated cells, we find that the AGM harbors two types of adult-repopulating HSCs upon explant culture: One type is BMP-activated and the other is a non-BMP-activated HSC type that is indirectly controlled by Hedgehog signaling through the VEGF pathway. Transcriptomic analyses demonstrate that the two HSC types express distinct but overlapping genetic programs. These results revealing the bifurcation in HSC types at early embryonic stages in the AGM explant model suggest that their development is dependent upon the signaling molecules in the microenvironment., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
46. Control of developmentally primed erythroid genes by combinatorial co-repressor actions.
- Author
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Stadhouders R, Cico A, Stephen T, Thongjuea S, Kolovos P, Baymaz HI, Yu X, Demmers J, Bezstarosti K, Maas A, Barroca V, Kockx C, Ozgur Z, van Ijcken W, Arcangeli ML, Andrieu-Soler C, Lenhard B, Grosveld F, and Soler E
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Carrier Proteins genetics, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Erythroid Cells cytology, Erythropoiesis, Humans, LIM Domain Proteins genetics, LIM Domain Proteins metabolism, Mice, Molecular Sequence Data, Nuclear Proteins genetics, Nuclear Receptor Co-Repressor 1 genetics, Nuclear Receptor Co-Repressor 1 metabolism, Nuclear Receptor Co-Repressor 2 genetics, Nuclear Receptor Co-Repressor 2 metabolism, Repressor Proteins genetics, Transcription Factors genetics, Transcription Factors metabolism, Tumor Suppressor Proteins genetics, Carrier Proteins metabolism, Erythroid Cells metabolism, Gene Expression Regulation, Developmental, Nuclear Proteins metabolism, Repressor Proteins metabolism, Tumor Suppressor Proteins metabolism
- Abstract
How transcription factors (TFs) cooperate within large protein complexes to allow rapid modulation of gene expression during development is still largely unknown. Here we show that the key haematopoietic LIM-domain-binding protein-1 (LDB1) TF complex contains several activator and repressor components that together maintain an erythroid-specific gene expression programme primed for rapid activation until differentiation is induced. A combination of proteomics, functional genomics and in vivo studies presented here identifies known and novel co-repressors, most notably the ETO2 and IRF2BP2 proteins, involved in maintaining this primed state. The ETO2-IRF2BP2 axis, interacting with the NCOR1/SMRT co-repressor complex, suppresses the expression of the vast majority of archetypical erythroid genes and pathways until its decommissioning at the onset of terminal erythroid differentiation. Our experiments demonstrate that multimeric regulatory complexes feature a dynamic interplay between activating and repressing components that determines lineage-specific gene expression and cellular differentiation.
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- 2015
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47. Corrigendum: BMP signalling differentially regulates distinct haematopoietic stem cell types.
- Author
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Crisan M, Kartalaei PS, Vink CS, Yamada-Inagawa T, Bollerot K, van IJcken W, van der Linden R, de Sousa Lopes SMC, Monteiro R, Mummery C, and Dzierzak E
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- 2015
- Full Text
- View/download PDF
48. BMP signalling differentially regulates distinct haematopoietic stem cell types.
- Author
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Crisan M, Kartalaei PS, Vink CS, Yamada-Inagawa T, Bollerot K, van IJcken W, van der Linden R, de Sousa Lopes SM, Monteiro R, Mummery C, and Dzierzak E
- Subjects
- Animals, Benzofurans, Bone Morphogenetic Proteins genetics, Embryo, Mammalian, Female, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Male, Mice, Mice, Transgenic, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Nuclear Proteins genetics, Nuclear Proteins metabolism, Quinolines, Bone Morphogenetic Proteins metabolism, Gene Expression Regulation, Developmental physiology, Hematopoietic Stem Cells physiology, Signal Transduction physiology
- Abstract
Adult haematopoiesis is the outcome of distinct haematopoietic stem cell (HSC) subtypes with self-renewable repopulating ability, but with different haematopoietic cell lineage outputs. The molecular basis for this heterogeneity is largely unknown. BMP signalling regulates HSCs as they are first generated in the aorta-gonad-mesonephros region, but at later developmental stages, its role in HSCs is controversial. Here we show that HSCs in murine fetal liver and the bone marrow are of two types that can be prospectively isolated--BMP activated and non-BMP activated. Clonal transplantation demonstrates that they have distinct haematopoietic lineage outputs. Moreover, the two HSC types differ in intrinsic genetic programs, thus supporting a role for the BMP signalling axis in the regulation of HSC heterogeneity and lineage output. Our findings provide insight into the molecular control mechanisms that define HSC types and have important implications for reprogramming cells to HSC fate and treatments targeting distinct HSC types.
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- 2015
- Full Text
- View/download PDF
49. A new CRB1 rat mutation links Müller glial cells to retinal telangiectasia.
- Author
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Zhao M, Andrieu-Soler C, Kowalczuk L, Paz Cortés M, Berdugo M, Dernigoghossian M, Halili F, Jeanny JC, Goldenberg B, Savoldelli M, El Sanharawi M, Naud MC, van Ijcken W, Pescini-Gobert R, Martinet D, Maass A, Wijnholds J, Crisanti P, Rivolta C, and Behar-Cohen F
- Subjects
- Age Factors, Animals, Animals, Newborn, Cells, Cultured, Disease Models, Animal, Electroretinography, Ependymoglial Cells metabolism, Ependymoglial Cells ultrastructure, Eye Proteins metabolism, Fluorescein Angiography, Glial Fibrillary Acidic Protein metabolism, Neurons pathology, Neurons ultrastructure, Platelet Endothelial Cell Adhesion Molecule-1 metabolism, Rats, Rats, Mutant Strains, Retinal Vessels pathology, Retinal Vessels ultrastructure, Signal Transduction physiology, Visual Pathways pathology, Visual Pathways ultrastructure, Ependymoglial Cells pathology, Eye Proteins genetics, Mutation genetics, Retinal Degeneration etiology, Retinal Degeneration genetics, Retinal Degeneration pathology, Telangiectasis complications, Telangiectasis genetics
- Abstract
We have identified and characterized a spontaneous Brown Norway from Janvier rat strain (BN-J) presenting a progressive retinal degeneration associated with early retinal telangiectasia, neuronal alterations, and loss of retinal Müller glial cells resembling human macular telangiectasia type 2 (MacTel 2), which is a retinal disease of unknown cause. Genetic analyses showed that the BN-J phenotype results from an autosomal recessive indel novel mutation in the Crb1 gene, causing dislocalization of the protein from the retinal Müller glia (RMG)/photoreceptor cell junction. The transcriptomic analyses of primary RMG cultures allowed identification of the dysregulated pathways in BN-J rats compared with wild-type BN rats. Among those pathways, TGF-β and Kit Receptor Signaling, MAPK Cascade, Growth Factors and Inflammatory Pathways, G-Protein Signaling Pathways, Regulation of Actin Cytoskeleton, and Cardiovascular Signaling were found. Potential molecular targets linking RMG/photoreceptor interaction with the development of retinal telangiectasia are identified. This model can help us to better understand the physiopathologic mechanisms of MacTel 2 and other retinal diseases associated with telangiectasia., (Copyright © 2015 the authors 0270-6474/15/356093-14$15.00/0.)
- Published
- 2015
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50. Global quantitative proteomics reveals novel factors in the ecdysone signaling pathway in Drosophila melanogaster.
- Author
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Sap KA, Bezstarosti K, Dekkers DH, van den Hout M, van Ijcken W, Rijkers E, and Demmers JA
- Subjects
- Animals, Drosophila Proteins analysis, Isotope Labeling, Mass Spectrometry, Proteome analysis, Proteomics, Transcriptome, Drosophila Proteins metabolism, Drosophila melanogaster metabolism, Ecdysone metabolism, Proteome metabolism, Signal Transduction physiology
- Abstract
The ecdysone signaling pathway plays a major role in various developmental transitions in insects. Recent advances in the understanding of ecdysone action have relied to a large extent on the application of molecular genetic tools in Drosophila. Here, we used a comprehensive quantitative SILAC MS-based approach to study the global, dynamic proteome of a Drosophila cell line to investigate how hormonal signals are transduced into specific cellular responses. Global proteome data after ecdysone treatment after various time points were then integrated with transcriptome data. We observed a substantial overlap in terms of affected targets between the dynamic proteome and transcriptome, although there were some clear differences in timing effects. Also, downregulation of several specific mRNAs did not always correlate with downregulation of their corresponding protein counterparts, and in some cases there was no correlation between transcriptome and proteome dynamics whatsoever. In addition, we performed a comprehensive interactome analysis of EcR, the major target of ecdysone. Proteins copurified with EcR include factors involved in transcription, chromatin remodeling, ecdysone signaling, ecdysone biosynthesis, and other signaling pathways. Novel ecdysone-responsive proteins identified in this study might link previously unknown proteins to the ecdysone signaling pathway and might be novel targets for developmental studies. To our knowledge, this is the first time that ecdysone signaling is studied by global quantitative proteomics. All MS data have been deposited in the ProteomeXchange with identifier PXD001455 (http://proteomecentral.proteomexchange.org/dataset/PXD001455)., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2015
- Full Text
- View/download PDF
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