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2. Seasonal variation in BCG-induced trained immunity

Author

Kilic, Gizem, Debisarun, Priya A., Alaswad, Ahmed, Baltissen, Marijke P., Lamers, Lieke A., de Bree, L. Charlotte J., Benn, Christine S., Aaby, Peter, Dijkstra, Helga, Lemmers, Heidi, Martens, Joost H.A., Domínguez-Andrés, Jorge, van Crevel, Reinout, Li, Yang, Xu, Cheng-Jian, and Netea, Mihai G.

Published
2024
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3. Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity.

Author

Baars, Matthijs JD, Douma, Thera, Simeonov, Dimitre R, Myers, Darienne R, Kulhanek, Kayla, Banerjee, Saikat, Zwakenberg, Susan, Baltissen, Marijke P, Amini, Mojtaba, de Roock, Sytze, van Wijk, Femke, Vermeulen, Michiel, Marson, Alexander, Roose, Jeroen P, and Vercoulen, Yvonne

Subjects
CD4-Positive T-Lymphocytes, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mice, Inflammation, Guanine Nucleotide Exchange Factors, DNA-Binding Proteins, Histones, Autoimmunity, Transcription, Genetic, Gene Expression Regulation, Core Binding Factor Alpha 2 Subunit, CRISPR-Cas Systems, RASGRP1, RUNX1, T cells, autoimmunity, transcription, Autoimmune Disease, Genetics, 2.1 Biological and endogenous factors, Inflammatory and immune system, Immunology
Abstract

RasGRP1 is a Ras guanine nucleotide exchange factor, and an essential regulator of lymphocyte receptor signaling. In mice, Rasgrp1 deletion results in defective T lymphocyte development. RASGRP1-deficient patients suffer from immune deficiency, and the RASGRP1 gene has been linked to autoimmunity. However, how RasGRP1 levels are regulated, and if RasGRP1 dosage alterations contribute to autoimmunity remains unknown. We demonstrate that diminished Rasgrp1 expression caused defective T lymphocyte selection in C57BL/6 mice, and that the severity of inflammatory disease inversely correlates with Rasgrp1 expression levels. In patients with autoimmunity, active inflammation correlated with decreased RASGRP1 levels in CD4+ T cells. By analyzing H3K27 acetylation profiles in human T cells, we identified a RASGRP1 enhancer that harbors autoimmunity-associated SNPs. CRISPR-Cas9 disruption of this enhancer caused lower RasGRP1 expression, and decreased binding of RUNX1 and CBFB transcription factors. Analyzing patients with autoimmunity, we detected reduced RUNX1 expression in CD4+ T cells. Lastly, we mechanistically link RUNX1 to transcriptional regulation of RASGRP1 to reveal a key circuit regulating RasGRP1 expression, which is vital to prevent inflammatory disease.

Published
2021

4. IRF8 is a transcriptional activator of CD37 expression in diffuse large B-cell lymphoma

Author

Elfrink, Suraya, ter Beest, Martin, Janssen, Luuk, Baltissen, Marijke P., Jansen, Pascal W.T.C., Kenyon, Angelique N., Steen, Raymond M., de Windt, Daynelys, Hagemann, Philipp M., Hess, Corine, van Spronsen, Dick-Johan, Hoevenaars, Brigiet, van der Spek, Ellen, Xu-Monette, Zijun Y., Young, Ken H., Kaffa, Charlotte, Bervoets, Sander, van Heek, Jolien, Hesius, Eva, de Winde, Charlotte M., Vermeulen, Michiel, van den Brand, Michiel, Scheijen, Blanca, and van Spriel, Annemiek B.

Published
2022
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6. Differences in Immune Responses in Individuals of Indian and European Origin: Relevance for the COVID-19 Pandemic

Author

Geckin, Büsra, primary, Zoodsma, Martijn, additional, Kilic, Gizem, additional, Debisarun, Priya A., additional, Rakshit, Srabanti, additional, Adiga, Vasista, additional, Ahmed, Asma, additional, Parthiban, Chaitra, additional, Kumar, Nirutha Chetan, additional, D’Souza, George, additional, Baltissen, Marijke P., additional, Martens, Joost H. A., additional, Domínguez-Andrés, Jorge, additional, Li, Yang, additional, Vyakarnam, Annapurna, additional, and Netea, Mihai G., additional

Published
2023
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9. Actin maturation requires the ACTMAP/C19orf54 protease

Author

Haahr, Peter, primary, Galli, Ricardo A., additional, van den Hengel, Lisa G., additional, Bleijerveld, Onno B., additional, Kazokaitė-Adomaitienė, Justina, additional, Song, Ji-Ying, additional, Kroese, Lona J., additional, Krimpenfort, Paul, additional, Baltissen, Marijke P., additional, Vermeulen, Michiel, additional, Ottenheijm, Coen A. C., additional, and Brummelkamp, Thijn R., additional

Published
2022
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10. Differences in anti-viral immune responses in individuals of Indian and European origin: relevance for the COVID-19 pandemic

Author

Geckin, Büsranur, primary, Zoodsma, Martijn, additional, Kilic, Gizem, additional, Debisarun, Priya A., additional, Rakshit, Srabanti, additional, Adiga, Vasista, additional, Ahmed, Asma, additional, Parthiban, Chaitra, additional, Kumar, Nirutha Chetan, additional, D’Souza, George, additional, Baltissen, Marijke P, additional, Martens, Joost H A, additional, Andres, Jorge Dominguez, additional, Li, Yang, additional, Vyakarnam, Annapurna, additional, and Netea, Mihai G, additional

Published
2022
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11. Functional annotation and investigation of the 10q24.33 melanoma risk locus identifies a common variant that influences transcriptional regulation of OBFC1

Author

Cardinale, Antonella, Cantalupo, Sueva, Lasorsa, Vito Alessandro, Montella, Annalaura, Cimmino, Flora, Succoio, Mariangela, Vermeulen, Michiel, Baltissen, Marijke P., Iolascon, Achille, Capasso, Mario, Cardinale, Antonella, Cantalupo, Sueva, Lasorsa, Vito Alessandro, Montella, Annalaura, Cimmino, Flora, Succoio, Mariangela, Vermeulen, Michiel, Baltissen, Marijke P., Iolascon, Achille, and Capasso, Mario

Abstract

Contains fulltext : 250105.pdf (Publisher’s version ) (Closed access)

Published
2022

12. Actin maturation requires the ACTMAP/C19orf54 protease

Author

Haahr, Peter, Galli, Ricardo A., van den Hengel, Lisa G., Bleijerveld, Onno B., Kazokaitė-Adomaitienė, Justina, Song, Ji Ying, Kroese, Lona J., Krimpenfort, Paul, Baltissen, Marijke P., Vermeulen, Michiel, Ottenheijm, Coen A.C., Brummelkamp, Thijn R., Haahr, Peter, Galli, Ricardo A., van den Hengel, Lisa G., Bleijerveld, Onno B., Kazokaitė-Adomaitienė, Justina, Song, Ji Ying, Kroese, Lona J., Krimpenfort, Paul, Baltissen, Marijke P., Vermeulen, Michiel, Ottenheijm, Coen A.C., and Brummelkamp, Thijn R.

Abstract

Protein synthesis generally starts with a methionine that is removed during translation. However, cytoplasmic actin defies this rule because its synthesis involves noncanonical excision of the acetylated methionine by an unidentified enzyme after translation. Here, we identified C19orf54, named ACTMAP (actin maturation protease), as this enzyme. Its ablation resulted in viable mice in which the cytoskeleton was composed of immature actin molecules across all tissues. However, in skeletal muscle, the lengths of sarcomeric actin filaments were shorter, muscle function was decreased, and centralized nuclei, a common hallmark of myopathies, progressively accumulated. Thus, ACTMAP encodes the missing factor required for the synthesis of mature actin and regulates specific actin-dependent traits in vivo.

Published
2022

13. Functional annotation and investigation of the 10q24.33 melanoma risk locus identifies a common variant that influences transcriptional regulation ofOBFC1

Author

Cardinale, Antonella, primary, Cantalupo, Sueva, additional, Lasorsa, Vito Alessandro, additional, Montella, Annalaura, additional, Cimmino, Flora, additional, Succoio, Mariangela, additional, Vermeulen, Michiel, additional, Baltissen, Marijke P, additional, Esposito, Matteo, additional, Avitabile, Marianna, additional, Formicola, Daniela, additional, Testori, Alessandro, additional, Bonfiglio, Ferdinando, additional, Ghiorzo, Paola, additional, Scalvenzi, Massimiliano, additional, Ayala, Fabrizio, additional, Zambrano, Nicola, additional, Iles, Mark M, additional, Xu, Mai, additional, Law, Matthew H, additional, Brown, Kevin M, additional, Iolascon, Achille, additional, and Capasso, Mario, additional

Published
2021
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14. Molecular mechanisms of bleeding disorderassociated GFI1BQ287* mutation and its affected pathways in megakaryocytes and platelets

Author

van Oorschot, Rinske, Hansen, Marten, Koornneef, Johanna M, Marneth, Anna E, Bergevoet, Saskia M, van Bergen, Maaike G J M, van Alphen, Floris P J, van der Zwaan, Carmen, Martens, Joost H A, Vermeulen, Michiel, Jansen, Pascal W T C, Baltissen, Marijke P A, Gorkom, Britta A P Laros-van, Janssen, Hans, Jansen, Joop H, von Lindern, Marieke, Meijer, Alexander B, van den Akker, Emile, van der Reijden, Bert A, Sub Biomol.Mass Spectrometry & Proteom., Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Academic Medical Center, AII - Inflammatory diseases, Landsteiner Laboratory, Sub Biomol.Mass Spectrometry & Proteom., Afd Biomol.Mass Spect. and Proteomics, and Biomolecular Mass Spectrometry and Proteomics

Subjects
Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Proteomics and Chromatin Biology, Megakaryocyte differentiation, Cellular differentiation, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Hematology, Biology, Cell biology, RCOR1, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Megakaryocyte, medicine, Platelet, Histone deacetylase, Induced pluripotent stem cell, Molecular Biology, 030215 immunology, Megakaryopoiesis
Abstract

Dominant-negative mutations in the transcription factor Growth Factor Independence-1B (GFI1B), such as GFI1BQ287*, cause a bleeding disorder characterized by a plethora of megakaryocyte and platelet abnormalities. The deregulated molecular mechanisms and pathways are unknown. Here we show that both normal and Q287* mutant GFI1B interacted most strongly with the lysine specific demethylase-1 - REST corepressor - histone deacetylase (LSD1-RCOR-HDAC) complex in megakaryoblasts. Sequestration of this complex by GFI1BQ287* and chemical separation of GFI1B from LSD1 induced abnormalities in normal megakaryocytes comparable to those seen in patients. Megakaryocytes derived from GFI1BQ287*-induced pluripotent stem cells also phenocopied abnormalities seen in patients. Proteome studies on normal and mutant-induced pluripotent stem cell-derived megakaryocytes identified a multitude of deregulated pathways downstream of GFI1BQ287* including cell division and interferon signaling. Proteome studies on platelets from GFI1BQ287* patients showed reduced expression of proteins implicated in platelet function, and elevated expression of proteins normally downregulated during megakaryocyte differentiation. Thus, GFI1B and LSD1 regulate a broad developmental program during megakaryopoiesis, and GFI1BQ287* deregulates this program through LSD1-RCOR-HDAC sequestering.

Published
2019

15. Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

Author

Wolf, Bas, primary, Oghabian, Ali, additional, Akinyi, Maureen V, additional, Hanks, Sandra, additional, Tromer, Eelco C, additional, Hooff, Jolien J E, additional, Voorthuijsen, Lisa, additional, Rooijen, Laura E, additional, Verbeeren, Jens, additional, Uijttewaal, Esther C H, additional, Baltissen, Marijke P A, additional, Yost, Shawn, additional, Piloquet, Philippe, additional, Vermeulen, Michiel, additional, Snel, Berend, additional, Isidor, Bertrand, additional, Rahman, Nazneen, additional, Frilander, Mikko J, additional, and Kops, Geert J P L, additional

Published
2021
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16. Functional annotation and investigation of the 10q24.33 melanoma risk locus identifies a common variant that influences transcriptional regulation of OBFC1

Author

Cardinale, Antonella, Cantalupo, Sueva, Lasorsa, Vito Alessandro, Montella, Annalaura, Cimmino, Flora, Succoio, Mariangela, Vermeulen, Michiel, Baltissen, Marijke P., Iolascon, Achille, Capasso, Mario, Cardinale, Antonella, Cantalupo, Sueva, Lasorsa, Vito Alessandro, Montella, Annalaura, Cimmino, Flora, Succoio, Mariangela, Vermeulen, Michiel, Baltissen, Marijke P., Iolascon, Achille, and Capasso, Mario

Abstract

Contains fulltext : 250105.pdf (Publisher’s version ) (Closed access)

Published
2021

17. Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

Author

Sub Bioinformatics, Theoretical Biology and Bioinformatics, de Wolf, Bas, Oghabian, Ali, Akinyi, Maureen V, Hanks, Sandra, Tromer, Eelco C, van Hooff, Jolien J E, van Voorthuijsen, Lisa, van Rooijen, Laura E, Verbeeren, Jens, Uijttewaal, Esther C H, Baltissen, Marijke P A, Yost, Shawn, Piloquet, Philippe, Vermeulen, Michiel, Snel, Berend, Isidor, Bertrand, Rahman, Nazneen, Frilander, Mikko J, Kops, Geert J P L, Sub Bioinformatics, Theoretical Biology and Bioinformatics, de Wolf, Bas, Oghabian, Ali, Akinyi, Maureen V, Hanks, Sandra, Tromer, Eelco C, van Hooff, Jolien J E, van Voorthuijsen, Lisa, van Rooijen, Laura E, Verbeeren, Jens, Uijttewaal, Esther C H, Baltissen, Marijke P A, Yost, Shawn, Piloquet, Philippe, Vermeulen, Michiel, Snel, Berend, Isidor, Bertrand, Rahman, Nazneen, Frilander, Mikko J, and Kops, Geert J P L

Published
2021

18. Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

Author

de Wolf, Bas, Oghabian, Ali, Akinyi, Maureen V, Hanks, Sandra, Tromer, Eelco C, van Hooff, Jolien J E, van Voorthuijsen, Lisa, van Rooijen, Laura E, Verbeeren, Jens, Uijttewaal, Esther C H, Baltissen, Marijke P A, Yost, Shawn, Piloquet, Philippe, Vermeulen, Michiel, Snel, Berend, Isidor, Bertrand, Rahman, Nazneen, Frilander, Mikko J, Kops, Geert J P L, de Wolf, Bas, Oghabian, Ali, Akinyi, Maureen V, Hanks, Sandra, Tromer, Eelco C, van Hooff, Jolien J E, van Voorthuijsen, Lisa, van Rooijen, Laura E, Verbeeren, Jens, Uijttewaal, Esther C H, Baltissen, Marijke P A, Yost, Shawn, Piloquet, Philippe, Vermeulen, Michiel, Snel, Berend, Isidor, Bertrand, Rahman, Nazneen, Frilander, Mikko J, and Kops, Geert J P L

Abstract

Aneuploidy is the leading cause of miscarriage and congenital birth defects, and a hallmark of cancer. Despite this strong association with human disease, the genetic causes of aneuploidy remain largely unknown. Through exome sequencing of patients with constitutional mosaic aneuploidy, we identified biallelic truncating mutations in CENATAC (CCDC84). We show that CENATAC is a novel component of the minor (U12-dependent) spliceosome that promotes splicing of a specific, rare minor intron subtype. This subtype is characterized by AT-AN splice sites and relatively high basal levels of intron retention. CENATAC depletion or expression of disease mutants resulted in excessive retention of AT-AN minor introns in ˜ 100 genes enriched for nucleocytoplasmic transport and cell cycle regulators, and caused chromosome segregation errors. Our findings reveal selectivity in minor intron splicing and suggest a link between minor spliceosome defects and constitutional aneuploidy in humans.

Published
2021

19. Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity

Author

CMM Sectie Molecular Cancer Research, CMM Groep Vercoulen, Cancer, CMM Groep Burgering, Immuno/reuma onderzoek 1 (Vastert), CTI Van Wijk, Child Health, Infection & Immunity, Baars, Matthijs J.D., Douma, Thera, Simeonov, Dimitre R., Myers, Darienne R., Kulhanek, Kayla, Banerjee, Saikat, Zwakenberg, Susan, Baltissen, Marijke P., Amini, Mojtaba, de Roock, Sytze, van Wijk, Femke, Vermeulen, Michiel, Marson, Alexander, Roose, Jeroen P., Vercoulen, Yvonne, CMM Sectie Molecular Cancer Research, CMM Groep Vercoulen, Cancer, CMM Groep Burgering, Immuno/reuma onderzoek 1 (Vastert), CTI Van Wijk, Child Health, Infection & Immunity, Baars, Matthijs J.D., Douma, Thera, Simeonov, Dimitre R., Myers, Darienne R., Kulhanek, Kayla, Banerjee, Saikat, Zwakenberg, Susan, Baltissen, Marijke P., Amini, Mojtaba, de Roock, Sytze, van Wijk, Femke, Vermeulen, Michiel, Marson, Alexander, Roose, Jeroen P., and Vercoulen, Yvonne

Published
2021

20. Trained immunity is regulated by T cell-induced CD40-TRAF6 signaling

Author

Jacobs, Maaike M.E., Maas, Rianne J.F., Jonkman, Inge, Negishi, Yutaka, Tielemans Zamora, Willem, Yanginlar, Cansu, van Heck, Julia, Matzaraki, Vasiliki, Martens, Joost H.A., Baltissen, Marijke, Vermeulen, Michiel, Morla-Folch, Judit, Ranzenigo, Anna, Wang, William, Umali, Martin, Ochando, Jordi, van der Vlag, Johan, Hilbrands, Luuk B., Joosten, Leo A.B., Netea, Mihai G., Mulder, Willem J.M., van Leent, Mandy M.T., Mhlanga, Musa M., Teunissen, Abraham J.P., Rother, Nils, and Duivenvoorden, Raphaël

Abstract

Trained immunity is characterized by histone modifications and metabolic changes in innate immune cells following exposure to inflammatory signals, leading to heightened responsiveness to secondary stimuli. Although our understanding of the molecular regulation of trained immunity has increased, the role of adaptive immune cells herein remains largely unknown. Here, we show that T cells modulate trained immunity via cluster of differentiation 40-tissue necrosis factor receptor-associated factor 6 (CD40-TRAF6) signaling. CD40-TRAF6 inhibition modulates functional, transcriptomic, and metabolic reprogramming and modifies histone 3 lysine 4 trimethylation associated with trained immunity. Besides in vitrostudies, we reveal that single-nucleotide polymorphisms in the proximity of CD40are linked to trained immunity responses in vivoand that combining CD40-TRAF6 inhibition with cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4-Ig)-mediated co-stimulatory blockade induces long-term graft acceptance in a murine heart transplantation model. Combined, our results reveal that trained immunity is modulated by CD40-TRAF6 signaling between myeloid and adaptive immune cells and that this can be leveraged for therapeutic purposes.

Published
2024
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21. The human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA

Author

Pinto, Rita, Vågbø, Cathrine B, Jakobsson, Magnus E, Kim, Yeji, Baltissen, Marijke P, O'Donohue, Marie-Françoise, Guzmán, Ulises H, Małecki, Jędrzej M, Wu, Jie, Kirpekar, Finn, Olsen, Jesper V, Gleizes, Pierre-Emmanuel, Vermeulen, Michiel, Leidel, Sebastian A, Slupphaug, Geir, Falnes, Pål Ø, Pinto, Rita, Vågbø, Cathrine B, Jakobsson, Magnus E, Kim, Yeji, Baltissen, Marijke P, O'Donohue, Marie-Françoise, Guzmán, Ulises H, Małecki, Jędrzej M, Wu, Jie, Kirpekar, Finn, Olsen, Jesper V, Gleizes, Pierre-Emmanuel, Vermeulen, Michiel, Leidel, Sebastian A, Slupphaug, Geir, and Falnes, Pål Ø

Abstract

RNA methylations are essential both for RNA structure and function, and are introduced by a number of distinct methyltransferases (MTases). In recent years, N6-methyladenosine (m6A) modification of eukaryotic mRNA has been subject to intense studies, and it has been demonstrated that m6A is a reversible modification that regulates several aspects of mRNA function. However, m6A is also found in other RNAs, such as mammalian 18S and 28S ribosomal RNAs (rRNAs), but the responsible MTases have remained elusive. 28S rRNA carries a single m6A modification, found at position A4220 (alternatively referred to as A4190) within a stem-loop structure, and here we show that the MTase ZCCHC4 is the enzyme responsible for introducing this modification. Accordingly, we found that ZCCHC4 localises to nucleoli, the site of ribosome assembly, and that proteins involved in RNA metabolism are overrepresented in the ZCCHC4 interactome. Interestingly, the absence of m6A4220 perturbs codon-specific translation dynamics and shifts gene expression at the translational level. In summary, we establish ZCCHC4 as the enzyme responsible for m6A modification of human 28S rRNA, and demonstrate its functional significance in mRNA translation.

Published
2020

23. Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity

Author

Baars, Matthijs J.D., primary, Douma, Thera, additional, Simeonov, Dimitre R., additional, Myers, Darienne R., additional, Kulhanek, Kayla, additional, Banerjee, Saikat, additional, Zwakenberg, Susan, additional, Baltissen, Marijke P., additional, Amini, Mojtaba, additional, Roock, Sytze, additional, Wijk, Femke, additional, Vermeulen, Michiel, additional, Marson, Alexander, additional, Roose, Jeroen P., additional, and Vercoulen, Yvonne, additional

Published
2020
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24. A central role for TFIID in the pluripotent transcription circuitry

Author

Pijnappel, Pim W. W. M., Esch, Daniel, Baltissen, Marijke P. A., Wu, Guangming, Mischerikow, Nikolai, Bergsma, Atze J., van der Wal, Erik, Han, Dong Wook, vom Bruch, Hermann, Moritz, Sören, Lijnzaad, Phillip, Altelaar, Maarten A. F., Sameith, Katrin, Zaehres, Holm, Heck, Albert J. R., Holstege, Frank C. P., Schöler, Hans R., and Timmers, Marc H. T.

Published
2013
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25. The rRNA m6A methyltransferase METTL5 is involved in pluripotency and developmental programs

Author

Ignatova, Valentina V., primary, Stolz, Paul, additional, Kaiser, Steffen, additional, Gustafsson, Tobias H., additional, Lastres, Palma Rico, additional, Sanz-Moreno, Adrián, additional, Cho, Yi-Li, additional, Amarie, Oana V., additional, Aguilar-Pimentel, Antonio, additional, Klein-Rodewald, Tanja, additional, Calzada-Wack, Julia, additional, Becker, Lore, additional, Marschall, Susan, additional, Kraiger, Markus, additional, Garrett, Lillian, additional, Seisenberger, Claudia, additional, Hölter, Sabine M., additional, Borland, Kayla, additional, Van De Logt, Erik, additional, Jansen, Pascal W.T.C., additional, Baltissen, Marijke P., additional, Valenta, Magdalena, additional, Vermeulen, Michiel, additional, Wurst, Wolfgang, additional, Gailus-Durner, Valerie, additional, Fuchs, Helmut, additional, Hrabe de Angelis, Martin, additional, Rando, Oliver J., additional, Kellner, Stefanie M., additional, Bultmann, Sebastian, additional, and Schneider, Robert, additional

Published
2020
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26. The human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA

Author

Pinto, Rita, primary, Vågbø, Cathrine B, additional, Jakobsson, Magnus E, additional, Kim, Yeji, additional, Baltissen, Marijke P, additional, O’Donohue, Marie-Françoise, additional, Guzmán, Ulises H, additional, Małecki, Jędrzej M, additional, Wu, Jie, additional, Kirpekar, Finn, additional, Olsen, Jesper V, additional, Gleizes, Pierre-Emmanuel, additional, Vermeulen, Michiel, additional, Leidel, Sebastian A, additional, Slupphaug, Geir, additional, and Falnes, Pål Ø, additional

Published
2019
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27. PRC2.1 and PRC2.2 Synergize to Coordinate H3K27 Trimethylation

Author

Healy, Evan, primary, Mucha, Marlena, additional, Glancy, Eleanor, additional, Fitzpatrick, Darren J., additional, Conway, Eric, additional, Neikes, Hannah K., additional, Monger, Craig, additional, Van Mierlo, Guido, additional, Baltissen, Marijke P., additional, Koseki, Yoko, additional, Vermeulen, Michiel, additional, Koseki, Haruhiko, additional, and Bracken, Adrian P., additional

Published
2019
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28. Molecular mechanisms of bleeding disorderassociated GFI1BQ287* mutation and its affected pathways in megakaryocytes and platelets

Author

Sub Biomol.Mass Spectrometry & Proteom., Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, van Oorschot, Rinske, Hansen, Marten, Koornneef, Johanna M, Marneth, Anna E, Bergevoet, Saskia M, van Bergen, Maaike G J M, van Alphen, Floris P J, van der Zwaan, Carmen, Martens, Joost H A, Vermeulen, Michiel, Jansen, Pascal W T C, Baltissen, Marijke P A, Gorkom, Britta A P Laros-van, Janssen, Hans, Jansen, Joop H, von Lindern, Marieke, Meijer, Alexander B, van den Akker, Emile, van der Reijden, Bert A, Sub Biomol.Mass Spectrometry & Proteom., Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, van Oorschot, Rinske, Hansen, Marten, Koornneef, Johanna M, Marneth, Anna E, Bergevoet, Saskia M, van Bergen, Maaike G J M, van Alphen, Floris P J, van der Zwaan, Carmen, Martens, Joost H A, Vermeulen, Michiel, Jansen, Pascal W T C, Baltissen, Marijke P A, Gorkom, Britta A P Laros-van, Janssen, Hans, Jansen, Joop H, von Lindern, Marieke, Meijer, Alexander B, van den Akker, Emile, and van der Reijden, Bert A

Published
2019

29. Deciphering lineage specification during early embryogenesis in mouse gastruloids using multilayered proteomics

Author

Stelloo, Suzan, Alejo-Vinogradova, Maria Teresa, van Gelder, Charlotte A.G.H., Zijlmans, Dick W., van Oostrom, Marek J., Valverde, Juan Manuel, Lamers, Lieke A., Rus, Teja, Sobrevals Alcaraz, Paula, Schäfers, Tilman, Furlan, Cristina, Jansen, Pascal W.T.C., Baltissen, Marijke P.A., Sonnen, Katharina F., Burgering, Boudewijn, Altelaar, Maarten A.F.M., Vos, Harmjan R., and Vermeulen, Michiel

Abstract

Gastrulation is a critical stage in embryonic development during which the germ layers are established. Advances in sequencing technologies led to the identification of gene regulatory programs that control the emergence of the germ layers and their derivatives. However, proteome-based studies of early mammalian development are scarce. To overcome this, we utilized gastruloids and a multilayered mass spectrometry-based proteomics approach to investigate the global dynamics of (phospho) protein expression during gastruloid differentiation. Our findings revealed many proteins with temporal expression and unique expression profiles for each germ layer, which we also validated using single-cell proteomics technology. Additionally, we profiled enhancer interaction landscapes using P300 proximity labeling, which revealed numerous gastruloid-specific transcription factors and chromatin remodelers. Subsequent degron-based perturbations combined with single-cell RNA sequencing (scRNA-seq) identified a critical role for ZEB2 in mouse and human somitogenesis. Overall, this study provides a rich resource for developmental and synthetic biology communities endeavoring to understand mammalian embryogenesis.

Published
2024
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30. Cross‐linking mass spectrometry reveals the structural topology of peripheral NuRD subunits relative to the core complex.

Author

Spruijt, Cornelia G., Gräwe, Cathrin, Kleinendorst, Simone C., Baltissen, Marijke P. A., and Vermeulen, Michiel

Subjects
MASS spectrometry, PROTEIN domains, TOPOLOGY, PROTEOMICS
Abstract

The multi‐subunit nucleosome remodeling and deacetylase (NuRD) complex consists of seven subunits, each of which comprises two or three paralogs in vertebrates. These paralogs define mutually exclusive and functionally distinct complexes. In addition, several proteins in the complex are multimeric, which complicates structural studies. Attempts to purify sufficient amounts of endogenous complex or recombinantly reconstitute the complex for structural studies have proven quite challenging. Until now, only substructures of individual domains or proteins and low‐resolution densities of (partial) complexes have been reported. In this study, we comprehensively investigated the relative orientation of different subunits within the NuRD complex using multiple cross‐link IP mass spectrometry (xIP‐MS) experiments. Our results confirm that the core of the complex is formed by MTA, RBBP, and HDAC proteins. Assembly of a copy of MBD and GATAD2 onto this core enables binding of the peripheral CHD and CDK2AP proteins. Furthermore, our experiments reveal that not only CDK2AP1 but also CDK2AP2 interacts with the NuRD complex. This interaction requires the C terminus of CHD proteins. Our data provide a more detailed understanding of the topology of the peripheral NuRD subunits relative to the core complex. Database: Proteomics data are available in the PRIDE database under the accession numbers PXD017244 and PXD017378. [ABSTRACT FROM AUTHOR]

Published
2021
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31. Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity

Author

Baars, Matthijs, primary, Douma, Thera, additional, Simeonov, Dimitre R., additional, Myers, Darienne R., additional, Banerjee, Saikat, additional, Kulhanek, Kayla, additional, Zwakenberg, Susan, additional, Baltissen, Marijke P., additional, de Roock, Sytze, additional, van Wijk, Femke, additional, Vermeulen, Michiel, additional, Marson, Alexander, additional, Roose, Jeroen P., additional, and Vercoulen, Yvonne, additional

Published
2019
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32. Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma

Author

Brien, Gerard L, primary, Remillard, David, additional, Shi, Junwei, additional, Hemming, Matthew L, additional, Chabon, Jonathon, additional, Wynne, Kieran, additional, Dillon, Eugène T, additional, Cagney, Gerard, additional, Van Mierlo, Guido, additional, Baltissen, Marijke P, additional, Vermeulen, Michiel, additional, Qi, Jun, additional, Fröhling, Stefan, additional, Gray, Nathanael S, additional, Bradner, James E, additional, Vakoc, Christopher R, additional, and Armstrong, Scott A, additional

Published
2018
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33. Quantitative mass spectrometry of TATA binding protein-containing complexes and subunit phosphorylations during the cell cycle

Author

Baltissen Marijke PA, Heck Albert JR, Kolkman Annemieke, Pijnappel WWM Pim, and Timmers HT Marc

Subjects
Cytology, QH573-671
Abstract

Abstract Background Progression through the cell cycle is accompanied by tightly controlled regulation of transcription. On one hand, a subset of genes is expressed in a cell cycle-dependent manner. On the other hand, a general inhibition of transcription occurs during mitosis. Genetic and genome-wide studies suggest cell cycle regulation at the level of transcription initiation by protein complexes containing the common DNA-binding subunit TATA binding protein (TBP). TBP is a key player in regulating transcription by all three nuclear RNA polymerases. It forms at least four distinct protein complexes with TBP-associated factors (TAFs): SL1, B-TFIID, TFIID, and TFIIIB. Some TAFs are known to remain associated with TBP during the cell cycle. Here we analyze all TAFs and their phosphorylation status during the cell cycle using a quantitative mass spectrometry approach. Results TBP protein complexes present in human cells at the G2/M and G1/S transitions were analyzed by combining affinity purification with quantitative mass spectrometry using stable isotope labeling with amino acids in cell culture (SILAC). Phosphorylations were mapped and quantified after enrichment of tryptic peptides by titanium dioxide. This revealed that subunit stoichiometries of TBP complexes remained intact, but their relative abundances in nuclear extracts changed during the cell cycle. Several novel phosphorylations were detected on subunits of the TBP complexes TFIID and SL1. G2/M-specific phosphorylations were detected on TAF1, TAF4, TAF7, and TAFI41/TAF1D, and G1/S-specific dephosphorylations were detected on TAF3. Many phosphorylated residues were evolutionary conserved from human to zebrafish and/or drosophila, and were present in conserved regions suggesting important regulatory functions. Conclusions This study provides the first quantitative proteomic analysis of human TBP containing protein complexes at the G2/M and G1/S transitions, and identifies new cell cycle-dependent phosphorylations on TAFs present in their protein complex. We speculate that phosphorylation of complex-specific subunits may be involved in regulating the activities of TBP protein complexes during the cell cycle.

Published
2009
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34. NuRD-interacting protein ZFP296 regulates genome-wide NuRD localization and differentiation of mouse embryonic stem cells

Author

Kloet, S.L., Karemaker, I.D., Voorthuijsen, L. van, Lindeboom, R.G.H., Baltissen, Marijke P., Edupuganti, Raghu R., Jansen, P.W.T.C., Vermeulen, Michiel, Kloet, S.L., Karemaker, I.D., Voorthuijsen, L. van, Lindeboom, R.G.H., Baltissen, Marijke P., Edupuganti, Raghu R., Jansen, P.W.T.C., and Vermeulen, Michiel

Abstract

Contains fulltext : 197898.pdf (publisher's version ) (Open Access)

Published
2018

36. Author response: Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma

Author

Brien, Gerard L, primary, Remillard, David, additional, Shi, Junwei, additional, Hemming, Matthew L, additional, Chabon, Jonathon, additional, Wynne, Kieran, additional, Dillon, Eugène T, additional, Cagney, Gerard, additional, Van Mierlo, Guido, additional, Baltissen, Marijke P, additional, Vermeulen, Michiel, additional, Qi, Jun, additional, Fröhling, Stefan, additional, Gray, Nathanael S, additional, Bradner, James E, additional, Vakoc, Christopher R, additional, and Armstrong, Scott A, additional

Published
2018
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38. Histone propionylation is a mark of active chromatin

Author

Kebede, Adam F, primary, Nieborak, Anna, additional, Shahidian, Lara Zorro, additional, Le Gras, Stephanie, additional, Richter, Florian, additional, Gómez, Diana Aguilar, additional, Baltissen, Marijke P, additional, Meszaros, Gergo, additional, Magliarelli, Helena de Fatima, additional, Taudt, Aaron, additional, Margueron, Raphael, additional, Colomé-Tatché, Maria, additional, Ricci, Romeo, additional, Daujat, Sylvain, additional, Vermeulen, Michiel, additional, Mittler, Gerhard, additional, and Schneider, Robert, additional

Published
2017
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39. N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis

Author

Edupuganti, Raghu R, primary, Geiger, Simon, additional, Lindeboom, Rik G H, additional, Shi, Hailing, additional, Hsu, Phillip J, additional, Lu, Zhike, additional, Wang, Shuang-Yin, additional, Baltissen, Marijke P A, additional, Jansen, Pascal W T C, additional, Rossa, Martin, additional, Müller, Markus, additional, Stunnenberg, Hendrik G, additional, He, Chuan, additional, Carell, Thomas, additional, and Vermeulen, Michiel, additional

Published
2017
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40. Trained immunity suppression determines kidney allograft survival

Author

Jonkman, Inge, Jacobs, Maaike M.E., Negishi, Yutaka, Yanginlar, Cansu, Martens, Joost H.A., Baltissen, Marijke, Vermeulen, Michiel, van den Hoogen, Martijn W.F., Baas, Marije, van der Vlag, Johan, Fayad, Zahi A., Teunissen, Abraham J.P., Madsen, Joren C., Ochando, Jordi, Joosten, Leo A.B., Netea, Mihai G., Mulder, Willem J.M., Mhlanga, Musa M., Hilbrands, Luuk B., Rother, Nils, and Duivenvoorden, Raphaël

Abstract

The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells with pretransplant and posttransplant serum of kidney transplant patients and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor and interleukin 6 cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected 1 week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity rarely experienced graft loss. This suppressive effect of posttransplant serum is likely mediated by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival.

Published
2024
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41. Recruitment of the mammalian histone-modifying EMSY complex to target genes is regulated by ZNF131

Author

Varier, Radhika A., De Santa Pau, Enrique Carrillo, van der Groep, Petra, Lindeboom, Rik G H, Matarese, Filomena, Mensinga, Anneloes, Smits, Arne H., Edupuganti, Raghu Ram, Baltissen, Marijke P., Jansen, Pascal W T C, Hoeve, Natalie Ter, Van Weely, Danny R., Poser, Ina, Van Diest, Paul J., Stunnenberg, Hendrik G., Vermeulen, Michiel, Varier, Radhika A., De Santa Pau, Enrique Carrillo, van der Groep, Petra, Lindeboom, Rik G H, Matarese, Filomena, Mensinga, Anneloes, Smits, Arne H., Edupuganti, Raghu Ram, Baltissen, Marijke P., Jansen, Pascal W T C, Hoeve, Natalie Ter, Van Weely, Danny R., Poser, Ina, Van Diest, Paul J., Stunnenberg, Hendrik G., and Vermeulen, Michiel

Published
2016

42. Recruitment of the mammalian histone-modifying EMSY complex to target genes is regulated by ZNF131

Author

Projecten, Cancer, Groep Timmers, Pathologie Laboratorium diagnostiek, Pathologie, Groep Vermeulen, Varier, Radhika A., De Santa Pau, Enrique Carrillo, van der Groep, Petra, Lindeboom, Rik G H, Matarese, Filomena, Mensinga, Anneloes, Smits, Arne H., Edupuganti, Raghu Ram, Baltissen, Marijke P., Jansen, Pascal W T C, Hoeve, Natalie Ter, Van Weely, Danny R., Poser, Ina, Van Diest, Paul J., Stunnenberg, Hendrik G., Vermeulen, Michiel, Projecten, Cancer, Groep Timmers, Pathologie Laboratorium diagnostiek, Pathologie, Groep Vermeulen, Varier, Radhika A., De Santa Pau, Enrique Carrillo, van der Groep, Petra, Lindeboom, Rik G H, Matarese, Filomena, Mensinga, Anneloes, Smits, Arne H., Edupuganti, Raghu Ram, Baltissen, Marijke P., Jansen, Pascal W T C, Hoeve, Natalie Ter, Van Weely, Danny R., Poser, Ina, Van Diest, Paul J., Stunnenberg, Hendrik G., and Vermeulen, Michiel

Published
2016

43. ZMYND8 Co-localizes with NuRD on Target Genes and Regulates Poly(ADP-Ribose)-Dependent Recruitment of GATAD2A/NuRD to Sites of DNA Damage

Author

Spruijt, Cornelia G., primary, Luijsterburg, Martijn S., additional, Menafra, Roberta, additional, Lindeboom, Rik G.H., additional, Jansen, Pascal W.T.C., additional, Edupuganti, Raghu Ram, additional, Baltissen, Marijke P., additional, Wiegant, Wouter W., additional, Voelker-Albert, Moritz C., additional, Matarese, Filomena, additional, Mensinga, Anneloes, additional, Poser, Ina, additional, Vos, Harmjan R., additional, Stunnenberg, Hendrik G., additional, van Attikum, Haico, additional, and Vermeulen, Michiel, additional

Published
2016
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44. Recruitment of the Mammalian Histone-modifying EMSY Complex to Target Genes Is Regulated by ZNF131

Author

Varier, Radhika A., primary, de Santa Pau, Enrique Carrillo, additional, van der Groep, Petra, additional, Lindeboom, Rik G.H., additional, Matarese, Filomena, additional, Mensinga, Anneloes, additional, Smits, Arne H., additional, Edupuganti, Raghu Ram, additional, Baltissen, Marijke P., additional, Jansen, Pascal W.T.C., additional, ter Hoeve, Natalie, additional, van Weely, Danny R., additional, Poser, Ina, additional, van Diest, Paul J., additional, Stunnenberg, Hendrik G., additional, and Vermeulen, Michiel, additional

Published
2016
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45. High-throughput identification of human SNPs affecting regulatory element activity

Author

Arensbergen, Joris, Pagie, Ludo, FitzPatrick, Vincent, Haas, Marcel, Baltissen, Marijke, Comoglio, Federico, Weide, Robin, Teunissen, Hans, Võsa, Urmo, Franke, Lude, Wit, Elzo, Vermeulen, Michiel, Bussemaker, Harmen, and Steensel, Bas

Abstract

Most of the millions of SNPs in the human genome are non-coding, and many overlap with putative regulatory elements. Genome-wide association studies (GWAS) have linked many of these SNPs to human traits or to gene expression levels, but rarely with sufficient resolution to identify the causal SNPs. Functional screens based on reporter assays have previously been of insufficient throughput to test the vast space of SNPs for possible effects on regulatory element activity. Here we leveraged the throughput and resolution of the survey of regulatory elements (SuRE) reporter technology to survey the effect of 5.9 million SNPs, including 57% of the known common SNPs, on enhancer and promoter activity. We identified more than 30,000 SNPs that alter the activity of putative regulatory elements, partially in a cell-type-specific manner. Integration of this dataset with GWAS results may help to pinpoint SNPs that underlie human traits. Application of SuRE reporter technology to survey the effect of 5.9 million SNPs in the human genome on enhancer and promoter activity identifies over 30,000 SNPs that alter the activity of putative regulatory elements.

Published
2019
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46. Proteomic landscape of the primary somatosensory cortex upon sensory deprivation.

Author

Kole, Koen, Lindeboom, Rik G. H., Baltissen, Marijke P. A., Jansen, Pascal W. T. C., Vermeulen, Michiel, Tiesinga, Paul, and Celikel, Tansu

Subjects
SOMATOSENSORY cortex, SENSORY neurons
Abstract

Experience-dependent plasticity (EDP) powerfully shapes neural circuits by inducing long-lasting molecular changes in the brain. Molecular mechanisms of EDP have been traditionally studied by identifying single or small subsets of targets along the biochemical pathways that link synaptic receptors to nuclear processes. Recent technological advances in large-scale analysis of gene transcription and translation now allow systematic observation of thousands of molecules simultaneously. Here we employed label-free quantitative mass spectrometry to address experience-dependent changes in the proteome after sensory deprivation of the primary somatosensory cortex. Cortical column- and layer-specific tissue samples were collected from control animals, with all whiskers intact, and animals whose C-row whiskers were bilaterally plucked for 11-14 days. Thirty-three samples from cortical layers (L) 2/3 and L4 spanning across control, deprived, and first- and second-order spared columns yielded at least 10 000 peptides mapping to ∼5000 protein groups. Of these, 4676 were identified with high confidence, and >3000 were found in all samples. This comprehensive database provides a snapshot of the proteome after whisker deprivation, a protocol that has been widely used to unravel the synaptic, cellular, and network mechanisms of EDP. Complementing the recently made available transcriptome for identical experimental conditions (see the accompanying article by Kole et al.), the database can be used to (i) mine novel targets whose translation is modulated by sensory organ use, (ii) cross-validate experimental protocols from the same developmental time point, and (iii) statistically map the molecular pathways of cortical plasticity at a columnar and laminar resolution. [ABSTRACT FROM AUTHOR]

Published
2017
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47. 1,25-Vitamin D3Deficiency Induces Albuminuria

Author

Sonneveld, Ramon, Hoenderop, Joost G.J., Stavenuiter, Andrea W.D., Ferrantelli, Evelina, Baltissen, Marijke P.A., Dijkman, Henry B., Florquin, Sandrine, Rops, Angelique L., Wetzels, Jack F.M., Berden, Jo H.M., van der Vlag, Johan, and Nijenhuis, Tom

Abstract

Vitamin D plays an important role in renal (patho)physiology. Patients with glomerular diseases have an injured renal filtration barrier, leading to proteinuria and reduced renal function. An impaired renal function also leads to 1,25-vitamin D3deficiency as a result of reduced renal 1α-hydroxylase activity. Vitamin D treatment to reduce proteinuria remains controversial, although there is an inverse correlation between vitamin D levels and proteinuria. Herein, we showed that 1,25-vitamin D3–deficient 25-hydroxy-vitamin-D3-1α-hydroxylase knockout mice and 1,25-vitamin D3–deficient rats develop podocyte injury and renal dysfunction. Glomerular injury was characterized by proteinuria and partial podocyte foot process effacement. Expression of nephrin, podocin, desmin, and transient receptor potential channel C6 in the podocyte was significantly altered in 1,25-vitamin D3–deficient animals. Supplementation with 1,25-vitamin D3or 1,25-vitamin D2prevented podocyte effacement or reversed glomerular and tubulointerstitial damage in 1,25-vitamin D3–deficient animals, thereby preserving and restoring renal function, respectively. The effect of 1,25-vitamin D3deficiency and 1,25-vitamin D3and 1,25-vitamin D2repletion on proteinuria could not be explained by hypocalcemia, changes in parathyroid hormone, or fibroblast growth factor 23. This study demonstrates that 1,25-vitamin D3deficiency directly leads to renal injury in rodents. Translated to human subjects, this would underline the need for early vitamin D supplementation in patients with glomerular disease and chronic renal insufficiency, which might inhibit or potentially reverse renal injury.

Published
2016
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48. Glucose Specifically Regulates TRPC6 Expression in the Podocyte in an AngII-Dependent Manner

Author

Sonneveld, Ramon, van der Vlag, Johan, Baltissen, Marijke P.A., Verkaart, Sjoerd A.J., Wetzels, Jack F.M., Berden, Jo H.M., Hoenderop, Joost G.J., and Nijenhuis, Tom

Abstract

Slit diaphragm and podocyte damage is crucial in the pathogenesis of proteinuria in diabetic nephropathy (DNP). Gain-of-function mutations in TRPC6, a slit diaphragm–associated ion channel, cause glomerulosclerosis; TRPC6 expression is increased in acquired glomerular disease. Hyperglycemia and high intrarenal angiotensin II (AngII) levels could contribute to podocyte injury in DNP. We determined whether glucose regulates TRPC6 expression and TRPC6-mediated Ca2+influx into the podocyte and whether these effects are AngII dependent. High glucose levels increased TRPC6 mRNA and protein expression in cultured podocytes; however, TRPC1 and TRPC5 mRNA expression was unaltered. AngII and inducing podocyte injury also specifically increased TRPC6 expression. Angiotensin receptor blockade and inhibition of local AngII production through angiotensin-converting enzyme inhibition prevented glucose-mediated increased TRPC6 expression. In addition, high glucose concentration pretreatment enhanced Ca2+influx in podocytes, which was prevented by concomitant angiotensin receptor blockade application and TRPC6 knockdown. Studies with a TRPC6luciferase promoter construct demonstrated a glucose concentration–dependent effect on TRPC6promoter activity. In vivo, podocyte TRPC6 protein expression was increased in proteinuric streptozotocin-induced diabetic rats. These data suggest that glucose can activate a local renin-angiotensin system in the podocyte, leading to increased TRPC6 expression, which enhances TRPC6-mediated Ca2+influx. Regulation of TRPC6 expression could be an important factor in podocyte injury due to chronic hyperglycemia and the antiproteinuric effect of angiotensin receptor blockade or angiotensin-converting enzyme inhibition in DNP.

Published
2014
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49. Hydroxychloroquine Inhibits the Trained Innate Immune Response to Interferons

Author

Rother, Nils, Yanginlar, Cansu, Lindeboom, Rik G.H., Bekkering, Siroon, van Leent, Mandy M.T., Buijsers, Baranca, Jonkman, Inge, de Graaf, Mark, Baltissen, Marijke, Lamers, Lieke A., Riksen, Niels P., Fayad, Zahi A., Mulder, Willem J.M., Hilbrands, Luuk B., Joosten, Leo A.B., Netea, Mihai G., Vermeulen, Michiel, van der Vlag, Johan, and Duivenvoorden, Raphaël

Abstract

Hydroxychloroquine is being investigated for a potential prophylactic effect in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but its mechanism of action is poorly understood. Circulating leukocytes from the blood of coronavirus disease 2019 (COVID-19) patients show increased responses to Toll-like receptor ligands, suggestive of trained immunity. By analyzing interferon responses of peripheral blood mononuclear cells from healthy donors conditioned with heat-killed Candida, trained innate immunity can be modeled in vitro. In this model, hydroxychloroquine inhibits the responsiveness of these innate immune cells to virus-like stimuli and interferons. This is associated with a suppression of histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation of inflammation-related genes, changes in the cellular lipidome, and decreased expression of interferon-stimulated genes. Our findings indicate that hydroxychloroquine inhibits trained immunity in vitro, which may not be beneficial for the antiviral innate immune response to SARS-CoV-2 infection in patients.

Published
2020
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50. The human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA

Author

Pinto, Rita, Vågbø, Cathrine B, Jakobsson, Magnus E, Kim, Yeji, Baltissen, Marijke P, O’Donohue, Marie-Françoise, Guzmán, Ulises H, Małecki, Jędrzej M, Wu, Jie, Kirpekar, Finn, Olsen, Jesper V, Gleizes, Pierre-Emmanuel, Vermeulen, Michiel, Leidel, Sebastian A, Slupphaug, Geir, and Falnes, Pål Ø

Subjects
2. Zero hunger, 540 Chemistry, 570 Life sciences, biology
Abstract

RNA methylations are essential both for RNA structure and function, and are introduced by a number of distinct methyltransferases (MTases). In recent years, N6-methyladenosine (m6A) modification of eukaryotic mRNA has been subject to intense studies, and it has been demonstrated that m6A is a reversible modification that regulates several aspects of mRNA function. However, m6A is also found in other RNAs, such as mammalian 18S and 28S ribosomal RNAs (rRNAs), but the responsible MTases have remained elusive. 28S rRNA carries a single m6A modification, found at position A4220 (alternatively referred to as A4190) within a stem-loop structure, and here we show that the MTase ZCCHC4 is the enzyme responsible for introducing this modification. Accordingly, we found that ZCCHC4 localises to nucleoli, the site of ribosome assembly, and that proteins involved in RNA metabolism are overrepresented in the ZCCHC4 interactome. Interestingly, the absence of m6A4220 perturbs codon-specific translation dynamics and shifts gene expression at the translational level. In summary, we establish ZCCHC4 as the enzyme responsible for m6A modification of human 28S rRNA, and demonstrate its functional significance in mRNA translation.

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