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1. De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders

Author

Jia, Xiangbin, primary, Zhang, Shujie, additional, Tan, Senwei, additional, Du, Bing, additional, He, Mei, additional, Qin, Haisong, additional, Chen, Jia, additional, Duan, Xinyu, additional, Luo, Jingsi, additional, Chen, Fei, additional, Ouyang, Luping, additional, Wang, Jian, additional, Chen, Guodong, additional, Yu, Bin, additional, Zhang, Ge, additional, Zhang, Zimin, additional, Lyu, Yongqing, additional, Huang, Yi, additional, Jiao, Jian, additional, Chen, Jin Yun (Helen), additional, Swoboda, Kathryn J., additional, Agolini, Emanuele, additional, Novelli, Antonio, additional, Leoni, Chiara, additional, Zampino, Giuseppe, additional, Cappuccio, Gerarda, additional, Brunetti-Pierri, Nicola, additional, Gerard, Benedicte, additional, Ginglinger, Emmanuelle, additional, Richer, Julie, additional, McMillan, Hugh, additional, White-Brown, Alexandre, additional, Hoekzema, Kendra, additional, Bernier, Raphael A., additional, Kurtz-Nelson, Evangeline C., additional, Earl, Rachel K., additional, Meddens, Claartje, additional, Alders, Marielle, additional, Fuchs, Meredith, additional, Caumes, Roseline, additional, Brunelle, Perrine, additional, Smol, Thomas, additional, Kuehl, Ryan, additional, Day-Salvatore, Debra-Lynn, additional, Monaghan, Kristin G., additional, Morrow, Michelle M., additional, Eichler, Evan E., additional, Hu, Zhengmao, additional, Yuan, Ling, additional, Tan, Jieqiong, additional, Xia, Kun, additional, Shen, Yiping, additional, and Guo, Hui, additional

Published
2022
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2. Regulatory DNA and Stem Cells in Complex Genetic Diseases

Author

Meddens, Claartje, Nieuwenhuis, EES, Mokry, Michal, University Utrecht, and Fuchs, S.A.

Subjects
regulatory DNA, IBD, Genetics, genomics
Abstract

Delineating the pathogenesis of complex genetic diseases is complicated by the great variety of genetic loci, genes, cell types, environmental factors and tissues that are involved. The genetic background of complex genetic diseases has been intensively studied through genome wide association studies (GWASs). This led to the association of many genetic loci to a multitude of diseases. The identification of causal variants and affected genes has proven difficult, thereby leaving some pathogenic mechanismsunresolved and potential therapeutic targets unrevealed. In this thesis, we study the involvement of DNA regulatory elements (DRE) in the pathogeneses of complex genetic diseases and epithelial mechanisms that are potentially involved in inflammatory bowel disease (IBD). In the first part of this thesis we studied loci associated to IBD, CVD cardiovascular diseases) and CKD (chronic kidney disease). We show that disease associated loci are enriched for active DRE and we used chromatin conformation capture to study the 3D configuration of these loci. Through this approach we identified many novel candidate genes, pathways and key regulators of IBD, CVD and CKD.Genetic studies on IBD have shown that the intestinal epithelium plays a important role in the pathogenesis of this complex genetic disease. Therefore, in the second part of this thesis, we use human intestinal organoids to study the interaction between bacterial antigens and the intestinal epithelium. We show that intestinal stem cells are a major source of the inflammatory response and that the responsiveness of the epithelium is regulated at the post-transcriptional level.

Published
2019

6. Non-coding DNA in IBD: From sequence variation in DNA regulatory elements to novel therapeutic potential

Author

Kinderdagcentrum Kameleon, MDL onderzoek 1, Child Health, Infection & Immunity, Regenerative Medicine and Stem Cells, Zorg en O&O, Onderzoek, Meddens, Claartje Aleid, Van Der List, Amy Catharina Johanna, Nieuwenhuis, Edward Eelco Salomon, Mokry, Michal, Kinderdagcentrum Kameleon, MDL onderzoek 1, Child Health, Infection & Immunity, Regenerative Medicine and Stem Cells, Zorg en O&O, Onderzoek, Meddens, Claartje Aleid, Van Der List, Amy Catharina Johanna, Nieuwenhuis, Edward Eelco Salomon, and Mokry, Michal

Published
2019

7. Regulatory DNA and Stem Cells in Complex Genetic Diseases

Author

Child Health, MDL onderzoek 1, Nieuwenhuis, Edward, Mokry, Michal, Meddens, Claartje, Fuchs, Sabine, Child Health, MDL onderzoek 1, Nieuwenhuis, Edward, Mokry, Michal, Meddens, Claartje, and Fuchs, Sabine

Published
2019

9. Stem Cells are the Principal Intestinal Epithelial Responders to Bacterial Antigens

Author

Meddens, Claartje A., primary, de Vries, Maaike H., additional, Hijma, Hemme J., additional, Berrens, Anne Claire, additional, Westendorp, Bart, additional, van der Spek, Jet, additional, Kooiman, Berend A. P., additional, Schreurs, Renée R. C. E., additional, Lijster, Erik, additional, Prelic, Sinisa, additional, Nieuwenhuis, Ninke M., additional, Mijnders, Marjolein, additional, Vega, Miguel, additional, Jansen, Suze A., additional, Hanemaaijer, Evelyn S., additional, Lansu, Nico, additional, van den Dungen, Noortje A. M., additional, Bunders, Madeleine J., additional, Middendorp, Sabine, additional, Clevers, Hans, additional, Mokry, Michal, additional, and Nieuwenhuis, Edward E. S., additional

Published
2019
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10. Chromatin Conformation Links Distal Target Genes to CKD Loci

Author

Brandt, Maarten M., Meddens, Claartje A., Louzao-Martinez, Laura, Van Den Dungen, Noortje A.M., Lansu, Nico R., Nieuwenhuis, Edward E.S., Duncker, Dirk J., Verhaar, Marianne C., Joles, Jaap A., Mokry, Michal, Cheng, Caroline, Brandt, Maarten M., Meddens, Claartje A., Louzao-Martinez, Laura, Van Den Dungen, Noortje A.M., Lansu, Nico R., Nieuwenhuis, Edward E.S., Duncker, Dirk J., Verhaar, Marianne C., Joles, Jaap A., Mokry, Michal, and Cheng, Caroline

Published
2018

11. Chromatin Conformation Links Distal Target Genes to CKD Loci

Author

MDL onderzoek 3, Child Health, Nefro Vasculaire Geneeskunde, Other research (not in main researchprogram), CMM Groep Cuppen, Zorg en O&O, Infection & Immunity, Regenerative Medicine and Stem Cells, Circulatory Health, MS Nefrologie, Experimentele Afd. Cardiologie 1, Brandt, Maarten M., Meddens, Claartje A., Louzao-Martinez, Laura, Van Den Dungen, Noortje A.M., Lansu, Nico R., Nieuwenhuis, Edward E.S., Duncker, Dirk J., Verhaar, Marianne C., Joles, Jaap A., Mokry, Michal, Cheng, Caroline, MDL onderzoek 3, Child Health, Nefro Vasculaire Geneeskunde, Other research (not in main researchprogram), CMM Groep Cuppen, Zorg en O&O, Infection & Immunity, Regenerative Medicine and Stem Cells, Circulatory Health, MS Nefrologie, Experimentele Afd. Cardiologie 1, Brandt, Maarten M., Meddens, Claartje A., Louzao-Martinez, Laura, Van Den Dungen, Noortje A.M., Lansu, Nico R., Nieuwenhuis, Edward E.S., Duncker, Dirk J., Verhaar, Marianne C., Joles, Jaap A., Mokry, Michal, and Cheng, Caroline

Published
2018

13. Chromatin Conformation Links Distal Target Genes to CKD Loci

Author

Brandt, Maarten M., primary, Meddens, Claartje A., additional, Louzao-Martinez, Laura, additional, van den Dungen, Noortje A.M., additional, Lansu, Nico R., additional, Nieuwenhuis, Edward E.S., additional, Duncker, Dirk J., additional, Verhaar, Marianne C., additional, Joles, Jaap A., additional, Mokry, Michal, additional, and Cheng, Caroline, additional

Published
2017
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14. Additional Candidate Genes for Human Atherosclerotic Disease Identified Through Annotation Based on Chromatin Organization

Author

Haitjema, Saskia, Meddens, Claartje A., Van Der Laan, Sander W., Kofink, Daniel, Harakalova, Magdalena, Tragante, Vinicius, Foroughi Asl, Hassan, Van Setten, Jessica, Brandt, Maarten M., Bis, Joshua C., O'Donnell, Christopher, Cheng, Caroline, Hoefer, Imo E., Waltenberger, Johannes, Biessen, Erik A L, Jukema, J. Wouter, Doevendans, Pieter A.F.M., Nieuwenhuis, Edward E.S., Erdmann, Jeanette, Björkegren, Johan L M, Pasterkamp, Gerard, Asselbergs, Folkert W., Den Ruijter, Hester M., Mokry, Michal, Haitjema, Saskia, Meddens, Claartje A., Van Der Laan, Sander W., Kofink, Daniel, Harakalova, Magdalena, Tragante, Vinicius, Foroughi Asl, Hassan, Van Setten, Jessica, Brandt, Maarten M., Bis, Joshua C., O'Donnell, Christopher, Cheng, Caroline, Hoefer, Imo E., Waltenberger, Johannes, Biessen, Erik A L, Jukema, J. Wouter, Doevendans, Pieter A.F.M., Nieuwenhuis, Edward E.S., Erdmann, Jeanette, Björkegren, Johan L M, Pasterkamp, Gerard, Asselbergs, Folkert W., Den Ruijter, Hester M., and Mokry, Michal

Published
2017

15. Additional Candidate Genes for Human Atherosclerotic Disease Identified Through Annotation Based on Chromatin Organization

Author

Experimentele Afd. Cardiologie 1, MDL onderzoek 3, Child Health, Circulatory Health, Onderzoek Precision medicine, Planningssecretariaat HCK, Nefro Vasculaire Geneeskunde, Regenerative Medicine and Stem Cells, CDL Staf Research, CDL Arcadia, Team Medisch, Pathologie Groep Brosens, Zorg en O&O, Infection & Immunity, CDL Cluster Onderzoek en Onderwijs, Haitjema, Saskia, Meddens, Claartje A., Van Der Laan, Sander W., Kofink, Daniel, Harakalova, Magdalena, Tragante, Vinicius, Foroughi Asl, Hassan, Van Setten, Jessica, Brandt, Maarten M., Bis, Joshua C., O'Donnell, Christopher, Cheng, Caroline, Hoefer, Imo E., Waltenberger, Johannes, Biessen, Erik A L, Jukema, J. Wouter, Doevendans, Pieter A.F.M., Nieuwenhuis, Edward E.S., Erdmann, Jeanette, Björkegren, Johan L M, Pasterkamp, Gerard, Asselbergs, Folkert W., Den Ruijter, Hester M., Mokry, Michal, Experimentele Afd. Cardiologie 1, MDL onderzoek 3, Child Health, Circulatory Health, Onderzoek Precision medicine, Planningssecretariaat HCK, Nefro Vasculaire Geneeskunde, Regenerative Medicine and Stem Cells, CDL Staf Research, CDL Arcadia, Team Medisch, Pathologie Groep Brosens, Zorg en O&O, Infection & Immunity, CDL Cluster Onderzoek en Onderwijs, Haitjema, Saskia, Meddens, Claartje A., Van Der Laan, Sander W., Kofink, Daniel, Harakalova, Magdalena, Tragante, Vinicius, Foroughi Asl, Hassan, Van Setten, Jessica, Brandt, Maarten M., Bis, Joshua C., O'Donnell, Christopher, Cheng, Caroline, Hoefer, Imo E., Waltenberger, Johannes, Biessen, Erik A L, Jukema, J. Wouter, Doevendans, Pieter A.F.M., Nieuwenhuis, Edward E.S., Erdmann, Jeanette, Björkegren, Johan L M, Pasterkamp, Gerard, Asselbergs, Folkert W., Den Ruijter, Hester M., and Mokry, Michal

Published
2017

16. Additional Candidate Genes for Human Atherosclerotic Disease Identified Through Annotation Based on Chromatin Organization

Author

Haitjema, Saskia, primary, Meddens, Claartje A., additional, van der Laan, Sander W., additional, Kofink, Daniel, additional, Harakalova, Magdalena, additional, Tragante, Vinicius, additional, Foroughi Asl, Hassan, additional, van Setten, Jessica, additional, Brandt, Maarten M., additional, Bis, Joshua C., additional, O’Donnell, Christopher, additional, Cheng, Caroline, additional, Hoefer, Imo E., additional, Waltenberger, Johannes, additional, Biessen, Erik, additional, Jukema, J. Wouter, additional, Doevendans, Pieter A.F.M., additional, Nieuwenhuis, Edward E.S., additional, Erdmann, Jeanette, additional, Björkegren, Johan L.M., additional, Pasterkamp, Gerard, additional, Asselbergs, Folkert W., additional, den Ruijter, Hester M., additional, and Mokry, Michal, additional

Published
2017
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17. Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease

Author

Meddens, Claartje A., primary, Harakalova, Magdalena, additional, van den Dungen, Noortje A. M., additional, Foroughi Asl, Hassan, additional, Hijma, Hemme J., additional, Cuppen, Edwin P. J. G., additional, Björkegren, Johan L. M., additional, Asselbergs, Folkert W., additional, Nieuwenhuis, Edward E. S., additional, and Mokry, Michal, additional

Published
2016
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18. Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease

Author

Meddens, Claartje A, Harakalova, Magdalena, van den Dungen, Noortje A M, Foroughi Asl, Hassan, Hijma, Hemme J, Cuppen, Edwin P J G, Björkegren, Johan L M, Asselbergs, Folkert W, Nieuwenhuis, Edward E S, Mokry, Michal, Meddens, Claartje A, Harakalova, Magdalena, van den Dungen, Noortje A M, Foroughi Asl, Hassan, Hijma, Hemme J, Cuppen, Edwin P J G, Björkegren, Johan L M, Asselbergs, Folkert W, Nieuwenhuis, Edward E S, and Mokry, Michal

Published
2016

19. Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease

Author

MDL onderzoek 3, Child Health, Cardiologie Arts-onderzoekers, CMM, Circulatory Health, Cancer, Brain, Cardiologie, Zorg en O&O, Regenerative Medicine and Stem Cells, Infection & Immunity, Meddens, Claartje A, Harakalova, Magdalena, van den Dungen, Noortje A M, Foroughi Asl, Hassan, Hijma, Hemme J, Cuppen, Edwin P J G, Björkegren, Johan L M, Asselbergs, Folkert W, Nieuwenhuis, Edward E S, Mokry, Michal, MDL onderzoek 3, Child Health, Cardiologie Arts-onderzoekers, CMM, Circulatory Health, Cancer, Brain, Cardiologie, Zorg en O&O, Regenerative Medicine and Stem Cells, Infection & Immunity, Meddens, Claartje A, Harakalova, Magdalena, van den Dungen, Noortje A M, Foroughi Asl, Hassan, Hijma, Hemme J, Cuppen, Edwin P J G, Björkegren, Johan L M, Asselbergs, Folkert W, Nieuwenhuis, Edward E S, and Mokry, Michal

Published
2016

20. Many inflammatory bowel disease risk loci include regions that regulate gene expression in immune cells and the intestinal epithelium

Author

Mokry, Michal, Middendorp, Sabine, Wiegerinck, Caroline L, Witte, Merlijn, Teunissen, Hans, Meddens, Claartje A, Cuppen, Edwin, Clevers, Hans, Nieuwenhuis, Edward E S, Mokry, Michal, Middendorp, Sabine, Wiegerinck, Caroline L, Witte, Merlijn, Teunissen, Hans, Meddens, Claartje A, Cuppen, Edwin, Clevers, Hans, and Nieuwenhuis, Edward E S

Abstract

BACKGROUND & AIMS: The contribution of genetic factors to the pathogenesis of inflammatory bowel disease (IBD) has been established by twin, targeted-sequencing, and genome-wide association studies. These studies identified many risk loci, and research is underway to identify causal variants. These studies have focused mainly on protein-coding genes. We investigated other functional elements in the human genome, such as regulatory regions.METHODS: Using acetylated histone 3 lysine 27 chromatin immunoprecipitation and sequencing, we identified tens of thousands of potential regulatory regions that are active in intestinal epithelium (primary intestinal crypts and cultured organoids) isolated from resected material and from biopsies collected during ileo-colonoscopies and immune cells (monocytes, macrophages, CD34(+), CD4(+), and CD8(+)). We correlated these regions with susceptibility loci for IBD.RESULTS: We have generated acetylated histone 3 lysine 27 profiles from primary intestinal epithelium and cultured organoids, which we have made publically available. We found that 45 of 163 single nucleotide polymorphisms (SNPs) associated with IBD overlap specifically with active regulatory elements. In addition, by taking strong linkage disequilibrium into account, another 47 IBD-associated SNPs colocalized with active regulatory elements through other SNPs in their vicinity. Altogether, 92 of 163 IBD-associated SNPs correlated with distinct active regulatory elements-a frequency 2.5- to 3.5-fold greater than that expected from random sampling. The variations in these SNPs often create or disrupt known binding motifs; they might affect the binding of transcriptional regulators to alter expression of regulated genes.CONCLUSIONS: In addition to variants in protein coding genes, variants in noncoding DNA regulatory regions that are active in intestinal epithelium and immune cells are potentially involved in the pathogenesis of IBD.

Published
2014

23. De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders

Author

Xiangbin Jia, Shujie Zhang, Senwei Tan, Bing Du, Mei He, Haisong Qin, Jia Chen, Xinyu Duan, Jingsi Luo, Fei Chen, Luping Ouyang, Jian Wang, Guodong Chen, Bin Yu, Ge Zhang, Zimin Zhang, Yongqing Lyu, Yi Huang, Jian Jiao, Jin Yun (Helen) Chen, Kathryn J. Swoboda, Emanuele Agolini, Antonio Novelli, Chiara Leoni, Giuseppe Zampino, Gerarda Cappuccio, Nicola Brunetti-Pierri, Benedicte Gerard, Emmanuelle Ginglinger, Julie Richer, Hugh McMillan, Alexandre White-Brown, Kendra Hoekzema, Raphael A. Bernier, Evangeline C. Kurtz-Nelson, Rachel K. Earl, Claartje Meddens, Marielle Alders, Meredith Fuchs, Roseline Caumes, Perrine Brunelle, Thomas Smol, Ryan Kuehl, Debra-Lynn Day-Salvatore, Kristin G. Monaghan, Michelle M. Morrow, Evan E. Eichler, Zhengmao Hu, Ling Yuan, Jieqiong Tan, Kun Xia, Yiping Shen, Hui Guo, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Jia, Xiangbin, Zhang, Shujie, Tan, Senwei, Du, Bing, He, Mei, Qin, Haisong, Chen, Jia, Duan, Xinyu, Luo, Jingsi, Chen, Fei, Ouyang, Luping, Wang, Jian, Chen, Guodong, Yu, Bin, Zhang, Ge, Zhang, Zimin, Lyu, Yongqing, Huang, Yi, Jiao, Jian, Chen, Jin Yun Helen, Swoboda, Kathryn J, Agolini, Emanuele, Novelli, Antonio, Leoni, Chiara, Zampino, Giuseppe, Cappuccio, Gerarda, Brunetti-Pierri, Nicola, Gerard, Benedicte, Ginglinger, Emmanuelle, Richer, Julie, Mcmillan, Hugh, White-Brown, Alexandre, Hoekzema, Kendra, Bernier, Raphael A, Kurtz-Nelson, Evangeline C, Earl, Rachel K, Meddens, Claartje, Alders, Marielle, Fuchs, Meredith, Caumes, Roseline, Brunelle, Perrine, Smol, Thoma, Kuehl, Ryan, Day-Salvatore, Debra-Lynn, Monaghan, Kristin G, Morrow, Michelle M, Eichler, Evan E, Hu, Zhengmao, Yuan, Ling, Tan, Jieqiong, Xia, Kun, Shen, Yiping, and Guo, Hui

Subjects
Multidisciplinary, Animal, DNA Helicases, RNA Helicase, DNA Helicase, Stress Granule, Stress Granules, Mice, RNA Recognition Motif Proteins, Neurodevelopmental Disorders, RNA Recognition Motif Protein, Animals, Poly-ADP-Ribose Binding Proteins, RNA Helicases, Poly-ADP-Ribose Binding Protein
Abstract

Stress granules (SGs) are cytoplasmic assemblies in response to a variety of stressors. We report a new neurodevelopmental disorder (NDD) with common features of language problems, intellectual disability, and behavioral issues caused by de novo likely gene-disruptive variants in UBAP2L , which encodes an essential regulator of SG assembly. Ubap2l haploinsufficiency in mouse led to social and cognitive impairments accompanied by disrupted neurogenesis and reduced SG formation during early brain development. On the basis of data from 40,853 individuals with NDDs, we report a nominally significant excess of de novo variants within 29 genes that are not implicated in NDDs, including 3 essential genes ( G3BP1 , G3BP2 , and UBAP2L ) in the core SG interaction network. We validated that NDD-related de novo variants in newly implicated and known NDD genes, such as CAPRIN1 , disrupt the interaction of the core SG network and interfere with SG formation. Together, our findings suggest the common SG pathology in NDDs.

Published
2022

24. Chromatin Conformation Links Distal Target Genes to CKD Loci.

Author

Brandt MM, Meddens CA, Louzao-Martinez L, van den Dungen NAM, Lansu NR, Nieuwenhuis EES, Duncker DJ, Verhaar MC, Joles JA, Mokry M, and Cheng C

Subjects
Animals, Biosynthetic Pathways genetics, Cells, Cultured, Databases, Genetic, Endothelial Cells, Genetic Predisposition to Disease genetics, Genotype, Homeostasis genetics, Humans, Kidney Tubules, Mice, Polymorphism, Single Nucleotide, Quantitative Trait Loci, RNA, Messenger metabolism, Sequence Analysis, DNA methods, Chromatin chemistry, DNA chemistry, Nucleic Acid Conformation, Renal Insufficiency, Chronic genetics
Abstract

Genome-wide association studies (GWASs) have identified many genetic risk factors for CKD. However, linking common variants to genes that are causal for CKD etiology remains challenging. By adapting self-transcribing active regulatory region sequencing, we evaluated the effect of genetic variation on DNA regulatory elements (DREs). Variants in linkage with the CKD-associated single-nucleotide polymorphism rs11959928 were shown to affect DRE function, illustrating that genes regulated by DREs colocalizing with CKD-associated variation can be dysregulated and therefore, considered as CKD candidate genes. To identify target genes of these DREs, we used circular chromosome conformation capture (4C) sequencing on glomerular endothelial cells and renal tubular epithelial cells. Our 4C analyses revealed interactions of CKD-associated susceptibility regions with the transcriptional start sites of 304 target genes. Overlap with multiple databases confirmed that many of these target genes are involved in kidney homeostasis. Expression quantitative trait loci analysis revealed that mRNA levels of many target genes are genotype dependent. Pathway analyses showed that target genes were enriched in processes crucial for renal function, identifying dysregulated geranylgeranyl diphosphate biosynthesis as a potential disease mechanism. Overall, our data annotated multiple genes to previously reported CKD-associated single-nucleotide polymorphisms and provided evidence for interaction between these loci and target genes. This pipeline provides a novel technique for hypothesis generation and complements classic GWAS interpretation. Future studies are required to specify the implications of our dataset and further reveal the complex roles that common variants have in complex diseases, such as CKD., (Copyright © 2018 by the American Society of Nephrology.)

Published
2018
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