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171 results on '"Koplev, Simon"'

1. Tracing clonal cell plasticity in the microenvironment of pancreatic ductal adenocarcinoma

Author

Koplev, Simon, Gill, Michael B., Marioni, John, and Miller, Martin

Subjects
clonal expansion, cyclical imaging, epithelial-mesenchymal transition, epitope barcoding, pancreatic cancer, polyclonality, tumour microenvironment
Abstract

The pancreas may regenerate without stem cells by induction of cellular plasticity between differentiated cells. Although essential for the remarkable capacity for pancreas regeneration, this property entails a vulnerability to cancer through acinar-to-ductal metaplasia and dedifferentiation by epithelial-mesenchymal transition, which contributes in largely unknown ways to metastasis in pancreatic cancer. As with most solid tumours, pancreatic ductal adenocarcinoma develops at the interface of cellular plasticity, genomic instability, and tumour microenvironments. However, current methodologies of analysing tumour tissue are unable to measure these modalities jointly. Here, by developing a method for epitope barcoding measured by cyclical imaging of antibody binding with confocal microscopes, this thesis explores the utility of multicolour cell labelling to investigate how polyclonal cancer evolution relates to epithelial-mesenchymal transition. The assembled barcodes consist of combinations of epitopes attached to a fluorophore and a nuclear-localisation signal, which enables cell sorting, quantitative image analysis, and effective decoding by statistical analysis. Using subcutaneous mouse models of pancreatic cancer, this thesis demonstrates that isogenic epitope labelling can detect epithelial clonal expansion events co-localised with fibroblasts in the tumour microenvironment. The epitope barcode constructs were stably expressed in mouse tumours for at least 2-3 weeks, proving feasibility of multicolour lineage tracing with cyclical imaging. By amending the barcodes with 8bp tags sequenced with single-cell RNA-seq, transcriptomic scores for epithelial-mesenchymal transition showed evidence for selectional acquisition of epithelial lineages during subcutaneous colonisation. Such labelled isogenic cell populations were amenable to Luria-Delbrück fluctuation analysis detecting lineages with epigenetic inheritance of cell states. Altogether, epitope barcoding and cyclical imaging form a compelling experimental strategy for investigating the clonality of transdifferentiation in the microenvironment of pancreatic cancer.

Published
2023
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2. Shared and distinct pathways and networks genetically linked to coronary artery disease between human and mouse

Author

Kurt, Zeyneb, Cheng, Jenny, Barrere-Cain, Rio, McQuillen, Caden N, Saleem, Zara, Hsu, Neil, Jiang, Nuoya, Pan, Calvin, Franzén, Oscar, Koplev, Simon, Wang, Susanna, Björkegren, Johan, Lusis, Aldons J, Blencowe, Montgomery, and Yang, Xia

Subjects
Biological Sciences, Genetics, Heart Disease - Coronary Heart Disease, Biotechnology, Human Genome, Cardiovascular, Aging, Atherosclerosis, Heart Disease, 2.1 Biological and endogenous factors, Humans, Mice, Animals, Coronary Artery Disease, Gene Regulatory Networks, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, atherosclerosis, coronary artery disease, gene regulatory networks, multiomics, cross-species comparison, Human, Mouse, computational biology, human, mouse, systems biology, Biochemistry and Cell Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Mouse models have been used extensively to study human coronary artery disease (CAD) or atherosclerosis and to test therapeutic targets. However, whether mouse and human share similar genetic factors and pathogenic mechanisms of atherosclerosis has not been thoroughly investigated in a data-driven manner. We conducted a cross-species comparison study to better understand atherosclerosis pathogenesis between species by leveraging multiomics data. Specifically, we compared genetically driven and thus CAD-causal gene networks and pathways, by using human GWAS of CAD from the CARDIoGRAMplusC4D consortium and mouse GWAS of atherosclerosis from the Hybrid Mouse Diversity Panel (HMDP) followed by integration with functional multiomics human (STARNET and GTEx) and mouse (HMDP) databases. We found that mouse and human shared >75% of CAD causal pathways. Based on network topology, we then predicted key regulatory genes for both the shared pathways and species-specific pathways, which were further validated through the use of single cell data and the latest CAD GWAS. In sum, our results should serve as a much-needed guidance for which human CAD-causal pathways can or cannot be further evaluated for novel CAD therapies using mouse models.

Published
2023

3. Systems immunology-based drug repurposing framework to target inflammation in atherosclerosis

Author

Amadori, Letizia, Calcagno, Claudia, Fernandez, Dawn M., Koplev, Simon, Fernandez, Nicolas, Kaur, Ravneet, Mury, Pauline, Khan, Nayaab S, Sajja, Swathy, Shamailova, Roza, Cyr, Yannick, Jeon, Minji, Hill, Christopher A., Chong, Peik Sean, Naidu, Sonum, Sakurai, Ken, Ghotbi, Adam Ali, Soler, Raphael, Eberhardt, Natalia, Rahman, Adeeb, Faries, Peter, Moore, Kathryn J., Fayad, Zahi A., Ma’ayan, Avi, and Giannarelli, Chiara

Published
2023
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4. Integration of transcriptomes of senescent cell models with multi-tissue patient samples reveals reduced COL6A3 as an inducer of senescence

Author

Savić, Radoslav, Yang, Jialiang, Koplev, Simon, An, Mahru C., Patel, Priyanka L., O’Brien, Robert N., Dubose, Brittany N., Dodatko, Tetyana, Rogatsky, Eduard, Sukhavasi, Katyayani, Ermel, Raili, Ruusalepp, Arno, Houten, Sander M., Kovacic, Jason C., Stewart, Andrew F., Yohn, Christopher B., Schadt, Eric E., Laberge, Remi-Martin, Björkegren, Johan L.M., Tu, Zhidong, and Argmann, Carmen

Published
2023
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5. An integrative multiomic network model links lipid metabolism to glucose regulation in coronary artery disease.

Author

Cohain, Ariella, Barrington, William, Jordan, Daniel, Beckmann, Noam, Argmann, Carmen, Houten, Sander, Charney, Alexander, Ermel, Raili, Sukhavasi, Katyayani, Franzen, Oscar, Koplev, Simon, Whatling, Carl, Belbin, Gillian, Yang, Jialiang, Hao, Ke, Kenny, Eimear, Tu, Zhidong, Zhu, Jun, Gan, Li-Ming, Do, Ron, Giannarelli, Chiara, Kovacic, Jason, Ruusalepp, Arno, Lusis, Aldons, Bjorkegren, Johan, and Schadt, Eric

Subjects
Animals, Blood Glucose, Cholesterol, Coronary Artery Disease, Diabetes Mellitus, Type 2, Female, Gene Expression Regulation, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose, Humans, Hypercholesterolemia, Lipid Metabolism, Mice, Inbred C57BL, Models, Biological, Polymorphism, Single Nucleotide, Mice
Abstract

Elevated plasma cholesterol and type 2 diabetes (T2D) are associated with coronary artery disease (CAD). Individuals treated with cholesterol-lowering statins have increased T2D risk, while individuals with hypercholesterolemia have reduced T2D risk. We explore the relationship between lipid and glucose control by constructing network models from the STARNET study with sequencing data from seven cardiometabolic tissues obtained from CAD patients during coronary artery by-pass grafting surgery. By integrating gene expression, genotype, metabolomic, and clinical data, we identify a glucose and lipid determining (GLD) regulatory network showing inverse relationships with lipid and glucose traits. Master regulators of the GLD network also impact lipid and glucose levels in inverse directions. Experimental inhibition of one of the GLD network master regulators, lanosterol synthase (LSS), in mice confirms the inverse relationships to glucose and lipid levels as predicted by our model and provides mechanistic insights.

Published
2021

6. Loss of soluble guanylyl cyclase in platelets contributes to atherosclerotic plaque formation and vascular inflammation

Author

Mauersberger, Carina, Sager, Hendrik B., Wobst, Jana, Dang, Tan An, Lambrecht, Laura, Koplev, Simon, Stroth, Marlène, Bettaga, Noomen, Schlossmann, Jens, Wunder, Frank, Friebe, Andreas, Björkegren, Johan L. M., Dietz, Lisa, Maas, Sanne L., van der Vorst, Emiel P. C., Sandner, Peter, Soehnlein, Oliver, Schunkert, Heribert, and Kessler, Thorsten

Published
2022
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7. Publisher Correction: Systems immunology-based drug repurposing framework to target inflammation in atherosclerosis

Author

Amadori, Letizia, Calcagno, Claudia, Fernandez, Dawn M., Koplev, Simon, Fernandez, Nicolas, Kaur, Ravneet, Mury, Pauline, Khan, Nayaab S, Sajja, Swathy, Shamailova, Roza, Cyr, Yannick, Jeon, Minji, Hill, Christopher A., Chong, Peik Sean, Naidu, Sonum, Sakurai, Ken, Ghotbi, Adam Ali, Soler, Raphael, Eberhardt, Natalia, Rahman, Adeeb, Faries, Peter, Moore, Kathryn J., Fayad, Zahi A., Ma’ayan, Avi, and Giannarelli, Chiara

Published
2023
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8. Publisher Correction: Transcriptome-wide association study of coronary artery disease identifies novel susceptibility genes

Author

Li, Ling, Chen, Zhifen, von Scheidt, Moritz, Li, Shuangyue, Steiner, Andrea, Güldener, Ulrich, Koplev, Simon, Ma, Angela, Hao, Ke, Pan, Calvin, Lusis, Aldons J., Pang, Shichao, Kessler, Thorsten, Ermel, Raili, Sukhavasi, Katyayani, Ruusalepp, Arno, Gagneur, Julien, Erdmann, Jeanette, Kovacic, Jason C., Björkegren, Johan L. M., and Schunkert, Heribert

Published
2022
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9. Transcriptome-wide association study of coronary artery disease identifies novel susceptibility genes

Author

Li, Ling, Chen, Zhifen, von Scheidt, Moritz, Li, Shuangyue, Steiner, Andrea, Güldener, Ulrich, Koplev, Simon, Ma, Angela, Hao, Ke, Pan, Calvin, Lusis, Aldons J., Pang, Shichao, Kessler, Thorsten, Ermel, Raili, Sukhavasi, Katyayani, Ruusalepp, Arno, Gagneur, Julien, Erdmann, Jeanette, Kovacic, Jason C., Björkegren, Johan L. M., and Schunkert, Heribert

Published
2022
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10. A mechanistic framework for cardiometabolic and coronary artery diseases

Author

Koplev, Simon, Seldin, Marcus, Sukhavasi, Katyayani, Ermel, Raili, Pang, Shichao, Zeng, Lingyao, Bankier, Sean, Di Narzo, Antonio, Cheng, Haoxiang, Meda, Vamsidhar, Ma, Angela, Talukdar, Husain, Cohain, Ariella, Amadori, Letizia, Argmann, Carmen, Houten, Sander M., Franzén, Oscar, Mocci, Giuseppe, Meelu, Omar A., Ishikawa, Kiyotake, Whatling, Carl, Jain, Anamika, Jain, Rajeev Kumar, Gan, Li-Ming, Giannarelli, Chiara, Roussos, Panos, Hao, Ke, Schunkert, Heribert, Michoel, Tom, Ruusalepp, Arno, Schadt, Eric E., Kovacic, Jason C., Lusis, Aldon J., and Björkegren, Johan L. M.

Published
2022
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11. JCAD, a Gene at the 10p11 Coronary Artery Disease Locus, Regulates Hippo Signaling in Endothelial Cells.

Author

Jones, Peter, Kaiser, Michael, Ghaderi Najafabadi, Maryam, Koplev, Simon, Zhao, Yuqi, Douglas, Gillian, Kyriakou, Theodosios, Andrews, Sarah, Rajmohan, Rathinasabapathy, Watkins, Hugh, Channon, Keith, Ye, Shu, Yang, Xia, Björkegren, Johan, Samani, Nilesh, and Webb, Tom

Subjects
apoptosis, atherosclerosis, coronary artery disease, endothelium, phenotype, Adaptor Proteins, Signal Transducing, Apoptosis, Cell Adhesion, Cell Adhesion Molecules, Cell Movement, Cell Proliferation, Coculture Techniques, Coronary Artery Disease, HEK293 Cells, Hippo Signaling Pathway, Human Umbilical Vein Endothelial Cells, Humans, Monocytes, Neovascularization, Physiologic, Phenotype, Phosphoproteins, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases, Signal Transduction, THP-1 Cells, Transcription Factors, Tumor Suppressor Proteins, YAP-Signaling Proteins, rhoA GTP-Binding Protein
Abstract

Objective- A large number of genetic loci have been associated with risk of coronary artery disease (CAD) through genome-wide association studies, however, for most loci the underlying biological mechanism is unknown. Determining the molecular pathways and cellular processes affected by these loci will provide new insights into CAD pathophysiology and may lead to new therapies. The CAD-associated variants at 10p11.23 fall in JCAD, which encodes an endothelial junction protein, however, its molecular function in endothelial cells is not known. In this study, we characterize the molecular role of JCAD (junctional cadherin 5 associated) in endothelial cells. Approach and Results- We show that JCAD knockdown in endothelial cells affects key phenotypes related to atherosclerosis including proliferation, migration, apoptosis, tube formation, and monocyte binding. We demonstrate that JCAD interacts with LATS2 (large tumor suppressor kinase 2) and negatively regulates Hippo signaling leading to increased activity of YAP (yes-associated protein), the transcriptional effector of the pathway. We also show by double siRNA knockdown that the phenotypes caused by JCAD knockdown require LATS2 and that JCAD is involved in transmission of RhoA-mediated signals into the Hippo pathway. In human tissues, we find that the CAD-associated lead variant, rs2487928, is associated with expression of JCAD in arteries, including atherosclerotic arteries. Gene co-expression analyses across disease-relevant tissues corroborate our phenotypic findings and support the link between JCAD and Hippo signaling. Conclusions- Our results show that JCAD negatively regulates Hippo signaling in endothelial cells and we suggest that JCAD contributes to atherosclerosis by mediating YAP activity and contributing to endothelial dysfunction.

Published
2018

12. A Strategy for Discovery of Endocrine Interactions with Application to Whole-Body Metabolism.

Author

Rosenberg, Gregory, Meng, Yonghong, Pan, Calvin, Phuong, Thuy, Gharakhanian, Raffi, Che, Nam, Mäkinen, Selina, Shih, Diana, Civelek, Mete, Parks, Brian, Kim, Eric, Norheim, Frode, Chella Krishnan, Karthickeyan, Hasin-Brumshtein, Yehudit, Mehrabian, Margarete, Laakso, Markku, Drevon, Christian, Koistinen, Heikki, Tontonoz, Peter, Reue, Karen, Cantor, Rita, Björkegren, Johan, Koplev, Simon, Rajbhandari, Prashant, Lusis, Aldons, Seldin, Marcus, and Vergnes, Laurent

Subjects
Lipocalin-5, Notum, SPARC-related modular calcium binding 1, adipocyte beiging, cross-tissue communication, endocrine, inter-alpha-trypsin inhibitor heavy chain H5, mitochondria, pro-platelet basic protein, secreted peptides, skeletal muscle respiration, Adipose Tissue, Animals, Cells, Cultured, Endocrine System, Homeostasis, Lipocalins, Mice, Mice, Inbred C57BL, Mitochondria, Mitochondrial Proteins, Muscle, Skeletal, Proteomics
Abstract

Inter-tissue communication via secreted proteins has been established as a vital mechanism for proper physiologic homeostasis. Here, we report a bioinformatics framework using a mouse reference population, the Hybrid Mouse Diversity Panel (HMDP), which integrates global multi-tissue expression data and publicly available resources to identify and functionally annotate novel circuits of tissue-tissue communication. We validate this method by showing that we can identify known as well as novel endocrine factors responsible for communication between tissues. We further show the utility of this approach by identification and mechanistic characterization of two new endocrine factors. Adipose-derived Lipocalin-5 is shown to enhance skeletal muscle mitochondrial function, and liver-secreted Notum promotes browning of white adipose tissue, also known as beiging. We demonstrate the general applicability of the method by providing in vivo evidence for three additional novel molecules mediating tissue-tissue interactions.

Published
2018

13. A Strategy for Discovery of Endocrine Interactions with Application to Whole-Body Metabolism

Author

Seldin, Marcus M, Koplev, Simon, Rajbhandari, Prashant, Vergnes, Laurent, Rosenberg, Gregory M, Meng, Yonghong, Pan, Calvin, Phuong, Thuy MN, Gharakhanian, Raffi, Che, Nam, Mäkinen, Selina, Shih, Diana M, Civelek, Mete, Parks, Brian W, Kim, Eric D, Norheim, Frode, Krishnan, Karthickeyan Chella, Hasin-Brumshtein, Yehudit, Mehrabian, Margarete, Laakso, Markku, Drevon, Christian A, Koistinen, Heikki A, Tontonoz, Peter, Reue, Karen, Cantor, Rita M, Björkegren, Johan LM, and Lusis, Aldons J

Subjects
Digestive Diseases, Biotechnology, Underpinning research, 1.1 Normal biological development and functioning, Adipose Tissue, Animals, Cells, Cultured, Endocrine System, Homeostasis, Lipocalins, Mice, Mice, Inbred C57BL, Mitochondria, Mitochondrial Proteins, Muscle, Skeletal, Proteomics, Lipocalin-5, Notum, SPARC-related modular calcium binding 1, adipocyte beiging, cross-tissue communication, endocrine, inter-alpha-trypsin inhibitor heavy chain H5, mitochondria, pro-platelet basic protein, secreted peptides, skeletal muscle respiration, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Endocrinology & Metabolism
Abstract

Inter-tissue communication via secreted proteins has been established as a vital mechanism for proper physiologic homeostasis. Here, we report a bioinformatics framework using a mouse reference population, the Hybrid Mouse Diversity Panel (HMDP), which integrates global multi-tissue expression data and publicly available resources to identify and functionally annotate novel circuits of tissue-tissue communication. We validate this method by showing that we can identify known as well as novel endocrine factors responsible for communication between tissues. We further show the utility of this approach by identification and mechanistic characterization of two new endocrine factors. Adipose-derived Lipocalin-5 is shown to enhance skeletal muscle mitochondrial function, and liver-secreted Notum promotes browning of white adipose tissue, also known as "beiging." We demonstrate the general applicability of the method by providing in vivo evidence for three additional novel molecules mediating tissue-tissue interactions.

Published
2018

14. The Library of Integrated Network-Based Cellular Signatures NIH Program: System-Level Cataloging of Human Cells Response to Perturbations

Author

Keenan, Alexandra B, Jenkins, Sherry L, Jagodnik, Kathleen M, Koplev, Simon, He, Edward, Torre, Denis, Wang, Zichen, Dohlman, Anders B, Silverstein, Moshe C, Lachmann, Alexander, Kuleshov, Maxim V, Ma'ayan, Avi, Stathias, Vasileios, Terryn, Raymond, Cooper, Daniel, Forlin, Michele, Koleti, Amar, Vidovic, Dusica, Chung, Caty, Schürer, Stephan C, Vasiliauskas, Jouzas, Pilarczyk, Marcin, Shamsaei, Behrouz, Fazel, Mehdi, Ren, Yan, Niu, Wen, Clark, Nicholas A, White, Shana, Mahi, Naim, Zhang, Lixia, Kouril, Michal, Reichard, John F, Sivaganesan, Siva, Medvedovic, Mario, Meller, Jaroslaw, Koch, Rick J, Birtwistle, Marc R, Iyengar, Ravi, Sobie, Eric A, Azeloglu, Evren U, Kaye, Julia, Osterloh, Jeannette, Haston, Kelly, Kalra, Jaslin, Finkbiener, Steve, Li, Jonathan, Milani, Pamela, Adam, Miriam, Escalante-Chong, Renan, Sachs, Karen, Lenail, Alex, Ramamoorthy, Divya, Fraenkel, Ernest, Daigle, Gavin, Hussain, Uzma, Coye, Alyssa, Rothstein, Jeffrey, Sareen, Dhruv, Ornelas, Loren, Banuelos, Maria, Mandefro, Berhan, Ho, Ritchie, Svendsen, Clive N, Lim, Ryan G, Stocksdale, Jennifer, Casale, Malcolm S, Thompson, Terri G, Wu, Jie, Thompson, Leslie M, Dardov, Victoria, Venkatraman, Vidya, Matlock, Andrea, Van Eyk, Jennifer E, Jaffe, Jacob D, Papanastasiou, Malvina, Subramanian, Aravind, Golub, Todd R, Erickson, Sean D, Fallahi-Sichani, Mohammad, Hafner, Marc, Gray, Nathanael S, Lin, Jia-Ren, Mills, Caitlin E, Muhlich, Jeremy L, Niepel, Mario, Shamu, Caroline E, Williams, Elizabeth H, Wrobel, David, Sorger, Peter K, Heiser, Laura M, Gray, Joe W, Korkola, James E, Mills, Gordon B, LaBarge, Mark, Feiler, Heidi S, Dane, Mark A, Bucher, Elmar, Nederlof, Michel, Sudar, Damir, and Gross, Sean

Subjects
Bioengineering, Cancer, Genetics, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Generic health relevance, Good Health and Well Being, Cataloging, Computational Biology, Databases, Chemical, Gene Expression Profiling, Gene Library, Humans, Information Storage and Retrieval, National Health Programs, National Institutes of Health (U.S.), Systems Biology, Transcriptome, United States, BD2K, L1000, MCF10A, MEMA, P100, data integration, lincsprogram, lincsproject, systems biology, systems pharmacology, Biochemistry and Cell Biology
Abstract

The Library of Integrated Network-Based Cellular Signatures (LINCS) is an NIH Common Fund program that catalogs how human cells globally respond to chemical, genetic, and disease perturbations. Resources generated by LINCS include experimental and computational methods, visualization tools, molecular and imaging data, and signatures. By assembling an integrated picture of the range of responses of human cells exposed to many perturbations, the LINCS program aims to better understand human disease and to advance the development of new therapies. Perturbations under study include drugs, genetic perturbations, tissue micro-environments, antibodies, and disease-causing mutations. Responses to perturbations are measured by transcript profiling, mass spectrometry, cell imaging, and biochemical methods, among other assays. The LINCS program focuses on cellular physiology shared among tissues and cell types relevant to an array of diseases, including cancer, heart disease, and neurodegenerative disorders. This Perspective describes LINCS technologies, datasets, tools, and approaches to data accessibility and reusability.

Published
2018

15. Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade

Author

Wang, Ying, Nanda, Vivek, Direnzo, Daniel, Ye, Jianqin, Xiao, Sophia, Kojima, Yoko, Howe, Kathryn L., Jarr, Kai-Uwe, Flores, Alyssa M., Tsantilas, Pavlos, Tsao, Noah, Rao, Abhiram, Newmane, Alexandra A. C., Eberhard, Anne V., Priest, James R., Ruusalepp, Arno, Pasterkamp, Gerard, Maegdefessel, Lars, Miller, Clint L., Lind, Lars, Koplev, Simon, Björkegren, Johan L. M., Owense, Gary K., Ingelsson, Erik, Weissmanr, Irving L., and Leeper, Nicholas J.

Published
2020

16. Developing a framework for digital objects in the Big Data to Knowledge (BD2K) commons: Report from the Commons Framework Pilots workshop

Author

Jagodnik, Kathleen M, Koplev, Simon, Jenkins, Sherry L, Ohno-Machado, Lucila, Paten, Benedict, Schurer, Stephan C, Dumontier, Michel, Verborgh, Ruben, Bui, Alex, Ping, Peipei, McKenna, Neil J, Madduri, Ravi, Pillai, Ajay, and Ma'ayan, Avi

Subjects
Information and Computing Sciences, Library and Information Studies, Networking and Information Technology R&D (NITRD), Generic health relevance, Biomedical Research, Datasets as Topic, Humans, Information Dissemination, Knowledge, National Institutes of Health (U.S.), Translational Research, Biomedical, United States, Accessibility, Big Data, FAIR principles, Findability, Interoperability, Reusability, Biological Sciences, Medical and Health Sciences, Biomedical Engineering, Medical Informatics, Health services and systems, Applied computing
Abstract

The volume and diversity of data in biomedical research have been rapidly increasing in recent years. While such data hold significant promise for accelerating discovery, their use entails many challenges including: the need for adequate computational infrastructure, secure processes for data sharing and access, tools that allow researchers to find and integrate diverse datasets, and standardized methods of analysis. These are just some elements of a complex ecosystem that needs to be built to support the rapid accumulation of these data. The NIH Big Data to Knowledge (BD2K) initiative aims to facilitate digitally enabled biomedical research. Within the BD2K framework, the Commons initiative is intended to establish a virtual environment that will facilitate the use, interoperability, and discoverability of shared digital objects used for research. The BD2K Commons Framework Pilots Working Group (CFPWG) was established to clarify goals and work on pilot projects that address existing gaps toward realizing the vision of the BD2K Commons. This report reviews highlights from a two-day meeting involving the BD2K CFPWG to provide insights on trends and considerations in advancing Big Data science for biomedical research in the United States.

Published
2017

17. Developing a Framework for Digital Objects in the Big Data to Knowledge (BD2K) Commons: Report from the Commons Framework Pilots Workshop

Author

Jagodnik, Kathleen M., Koplev, Simon, Jenkins, Sherry, Ohno-Machado, Lucila, Paten, Benedict, Schurer, Stephan C., Dumontier, Michel, Verborgh, Ruben, Bui, Alex, Ping, Peipei, McKenna, Neil J., Madduri, Ravi, Pillai, Ajay, and Ma’ayan, Avi

Subjects
Accessibility, Big Data, FAIR Principles, Findability, Interoperability, Reusability
Abstract

The volume and diversity of data in biomedical research has been rapidly increasing in recent years. While such data hold significant promise for accelerating discovery, their use entails many challenges including: the need for adequate computational infrastructure, secure processes for data sharing and access, tools that allow researchers to find and integrate diverse datasets, and standardized methods of analysis. These are just some elements of a complex ecosystem that needs to be built to support the rapid accumulation of these data. The NIH Big Data to Knowledge (BD2K) initiative aims to facilitate digitally enabled biomedical research. Within the BD2K framework, the Commons initiative is intended to establish a virtual environment that will facilitate the use, interoperability, and discoverability of shared digital objects used for research. The BD2K Commons Framework Pilots Working Group (CFPWG) was established to clarify goals and work on pilot projects that would address existing gaps toward realizing the vision of the BD2K Commons. This report reviews highlights from a two-day meeting involving the BD2K CFPWG to provide insights on trends and considerations in advancing Big Data science for biomedical research in the United States.Graphical Abstract

Published
2017

18. Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis.

Author

Mocci, Giuseppe, Sukhavasi, Katyayani, Örd, Tiit, Bankier, Sean, Singha, Prosanta, Arasu, Uma Thanigai, Agbabiaje, Olayinka Oluwasegun, Mäkinen, Petri, Lijiang Ma, Hodonsky, Chani J., Aherrahrou, Redouane, Muhl, Lars, Jianping Liu, Gustafsson, Sonja, Byandelger, Byambajav, Ying Wang, Koplev, Simon, Lendahl, Urban, Owens, Gary K., and Leeper, Nicholas J.

Published
2024
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19. Author Response: Shared and distinct pathways and networks genetically linked to coronary artery disease between human and mouse

Author

Kurt, Zeyneb, primary, Cheng, Jenny, additional, Barrere-Cain, Rio, additional, McQuillen, Caden N, additional, Saleem, Zara, additional, Hsu, Neil, additional, Jiang, Nuoya, additional, Pan, Calvin, additional, Franzén, Oscar, additional, Koplev, Simon, additional, Wang, Susanna, additional, Björkegren, Johan LM, additional, Lusis, Aldons J, additional, Blencowe, Montgomery, additional, and Yang, Xia, additional

Published
2023
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20. Shared and distinct pathways and networks genetically linked to coronary artery disease between human and mouse

Author

Kurt, Zeyneb, primary, Cheng, Jenny, primary, Barrere-Cain, Rio, additional, McQuillen, Caden N, additional, Saleem, Zara, additional, Hsu, Neil, additional, Jiang, Nuoya, additional, Pan, Calvin, additional, Franzén, Oscar, additional, Koplev, Simon, additional, Wang, Susanna, additional, Björkegren, Johan, additional, Lusis, Aldons J, additional, Blencowe, Montgomery, additional, and Yang, Xia, additional

Published
2023
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21. Universal and tissue-specific fibroblasts in chronic inflammation and cancer.

Author

Koplev, Simon and Teichmann, Sarah A.

Subjects
*CELL communication, *CANCER cells, *IMMUNOSUPPRESSION, *INFLAMMATION, *TISSUES
Abstract

In this issue of Cancer Cell , Gao et al. map fibroblast diversity across tumors and chronic inflammatory tissues. The authors uncover universal fibroblast subtypes such as LRRC15+ and MMP1+ myofibroblasts along with specialized tissue-specific subtypes. They reveal cellular roles of fibroblasts in immunosuppression through stromal niches and cell-cell interactions. [ABSTRACT FROM AUTHOR]

Published
2024
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22. Unraveling tumor–immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy

Author

Jiménez-Sánchez, Alejandro, Cybulska, Paulina, Mager, Katherine LaVigne, Koplev, Simon, Cast, Oliver, Couturier, Dominique-Laurent, Memon, Danish, Selenica, Pier, Nikolovski, Ines, Mazaheri, Yousef, Bykov, Yonina, Geyer, Felipe C., Macintyre, Geoff, Gavarró, Lena Morrill, Drews, Ruben M., Gill, Michael B., Papanastasiou, Anastasios D., Sosa, Ramon E., Soslow, Robert A., Walther, Tyler, Shen, Ronglai, Chi, Dennis S., Park, Kay J., Hollmann, Travis, Reis-Filho, Jorge S., Markowetz, Florian, Beltrao, Pedro, Vargas, Hebert Alberto, Zamarin, Dmitriy, Brenton, James D., Snyder, Alexandra, Weigelt, Britta, Sala, Evis, and Miller, Martin L.

Published
2020
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25. A spatial human thymus cell atlas mapped to a continuous tissue axis

Author

Yayon, Nadav, primary, Kedlian, Veronika R., additional, Boehme, Lena, additional, Suo, Chenqu, additional, Wachter, Brianna, additional, Beuschel, Rebecca T., additional, Amsalem, Oren, additional, Polanski, Krzysztof, additional, Koplev, Simon, additional, Tuck, Elizabeth, additional, Dann, Emma, additional, Van Hulle, Jolien, additional, Perera, Shani, additional, Putteman, Tom, additional, Predeus, Alexander V., additional, Dabrowska, Monika, additional, Richardson, Laura, additional, Tudor, Catherine, additional, Kreins, Alexandra Y., additional, Engelbert, Justin, additional, Stephenson, Emily, additional, Kleshchevnikov, Vitalii, additional, De Rita, Fabrizio, additional, Crossland, David, additional, Bosticardo, Marita, additional, Pala, Francesca, additional, Prigmore, Elena, additional, Chipampe, Nana-Jane, additional, Prete, Martin, additional, Fei, Lijiang, additional, To, Ken, additional, Barker, Roger A., additional, He, Xiaoling, additional, Van Nieuwerburgh, Filip, additional, Bayraktar, Omer, additional, Patel, Minal, additional, Davies, Graham E., additional, Haniffa, Muzlifah A., additional, Uhlmann, Virginie, additional, Notarangelo, Luigi D., additional, Germain, Ronald N., additional, Radtke, Andrea J., additional, Marioni, John C., additional, Taghon, Tom, additional, and Teichmann, Sarah A., additional

Published
2023
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27. Functional and transcriptomic insights into pathogenesis of R9C phospholamban mutation using human induced pluripotent stem cell-derived cardiomyocytes

Author

Ceholski, Delaine K., Turnbull, Irene C., Kong, Chi-Wing, Koplev, Simon, Mayourian, Joshua, Gorski, Przemek A., Stillitano, Francesca, Skodras, Angelos A., Nonnenmacher, Mathieu, Cohen, Ninette, Björkegren, Johan L.M., Stroik, Daniel R., Cornea, Razvan L., Thomas, David D., Li, Ronald A., Costa, Kevin D., and Hajjar, Roger J.

Published
2018
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28. Histone deacetylase 9 promotes endothelial-mesenchymal transition and an unfavorable atherosclerotic plaque phenotype

Author

Lecce, Laura, Xu, Yang, V'Gangula, Bhargavi, Chandel, Nirupama, Pothula, Venu, Caudrillier, Axelle, Santini, Maria Paola, d'Escamard, Valentina, Ceholski, Delaine K., Gorski, Przemek A., Ma, Lijiang, Koplev, Simon, Bjorklund, Martin Maeng, Bjorkegren, Johan L.M., Boehm, Manfred, Bentzon, Jacob Fog, Fuster, Valentin, Kim, Ha Won, Weintraub, Neal L., Baker, Andrew H., Bernstein, Emily, and Kovacic, Jason C.

Subjects
Atherosclerotic plaque -- Development and progression -- Genetic aspects, Cardiovascular research, Stem cells -- Genetic aspects -- Health aspects, Cell differentiation -- Genetic aspects -- Health aspects, Epithelial cells -- Health aspects -- Genetic aspects, Phenotype -- Research, Health care industry
Abstract

Endothelial-mesenchymal transition (EndMT) is associated with various cardiovascular diseases and in particular with atherosclerosis and plaque instability. However, the molecular pathways that govern EndMT are poorly defined. Specifically, the role of epigenetic factors and histone deacetylases (HDACs) in controlling EndMT and the atherosclerotic plaque phenotype remains unclear. Here, we identified histone deacetylation, specifically that mediated by HDAC9 (a class Ila HDAC), as playing an important role in both EndMT and atherosclerosis. Using in vitro models, we found class Ila HDAC inhibition sustained the expression of endothelial proteins and mitigated the increase in mesenchymal proteins, effectively blocking EndMT. Similarly, ex vivo genetic knockout of Hdac9 in endothelial cells prevented EndMT and preserved a more endothelial-like phenotype. In vivo, atherosclerosis-prone mice with endothelial-specific Hdac9 knockout showed reduced EndMT and significantly reduced plaque area. Furthermore, these mice displayed a more favorable plaque phenotype, with reduced plaque lipid content and increased fibrous cap thickness. Together, these findings indicate that HDAC9 contributes to vascular pathology by promoting EndMT. Our study provides evidence for a pathological link among EndMT, HDAC9, and atherosclerosis and suggests that targeting of HDAC9 may be beneficial for plaque stabilization or slowing the progression of atherosclerotic disease., Introduction Endothelial-mesenchymal transition (EndMT) is an essential process during cardiac development, contributing to cardiac valve formation and the stabilization of new vasculature in the developing embryo (1, 2). EndMT also [...]

Published
2021
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29. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Author

Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten-Jacobs, Loes, Giese, Anne-Katrin, van der Laan, Sander W., Gretarsdottir, Solveig, Anderson, Christopher D., Chong, Michael, Adams, Hieab H. H., Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M., Benavente, Oscar R., Bevan, Steve, Boncoraglio, Giorgio B., Brown, Jr, Robert D., Butterworth, Adam S., Carrera, Caty, Carty, Cara L., Chasman, Daniel I., Chen, Wei-Min, Cole, John W., Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul I. W., DeStefano, Anita L., den Hoed, Marcel, Duan, Qing, Engelter, Stefan T., Falcone, Guido J., Gottesman, Rebecca F., Grewal, Raji P., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B., Hassan, Ahamad, Havulinna, Aki S., Heckbert, Susan R., Holliday, Elizabeth G., Howard, George, Hsu, Fang-Chi, Hyacinth, Hyacinth I., Ikram, M. Arfan, Ingelsson, Erik, Irvin, Marguerite R., Jian, Xueqiu, Jiménez-Conde, Jordi, Johnson, Julie A., Jukema, J. Wouter, Kanai, Masahiro, Keene, Keith L., Kissela, Brett M., Kleindorfer, Dawn O., Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A., Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Lee, Jin-Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M., Lin, Wei-Yu, Lindgren, Arne G., Lorentzen, Erik, Magnusson, Patrik K., Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F., Meschia, James F., Mitchell, Braxton D., Mosley, Thomas H., Nalls, Michael A., Ninomiya, Toshiharu, O’Donnell, Martin J., Psaty, Bruce M., Pulit, Sara L., Rannikmäe, Kristiina, Reiner, Alexander P., Rexrode, Kathryn M., Rice, Kenneth, Rich, Stephen S., Ridker, Paul M., Rost, Natalia S., Rothwell, Peter M., Rotter, Jerome I., Rundek, Tatjana, Sacco, Ralph L., Sakaue, Saori, Sale, Michele M., Salomaa, Veikko, Sapkota, Bishwa R., Schmidt, Reinhold, Schmidt, Carsten O., Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie L. M., Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D., Thijs, Vincent N. S., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, van Duijn, Cornelia M., Walters, Matthew, Wareham, Nicholas J., Wassertheil-Smoller, Sylvia, Wilson, James G., Wiggins, Kerri L., Yang, Qiong, Yusuf, Salim, Bis, Joshua C., Pastinen, Tomi, Ruusalepp, Arno, Schadt, Eric E., Koplev, Simon, Björkegren, Johan L. M., Codoni, Veronica, Civelek, Mete, Smith, Nicholas L., Trégouët, David A., Christophersen, Ingrid E., Roselli, Carolina, Lubitz, Steven A., Ellinor, Patrick T., Tai, E. Shyong, Kooner, Jaspal S., Kato, Norihiro, He, Jiang, van der Harst, Pim, Elliott, Paul, Chambers, John C., Takeuchi, Fumihiko, Johnson, Andrew D., Sanghera, Dharambir K., Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez-Cadenas, Israel, Longstreth, Jr, W. T., Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C., Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B., Kittner, Steven J., Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S., Howson, Joanna M. M., Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin

Published
2018
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30. Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Author

Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten-Jacobs, Loes, Giese, Anne-Katrin, van der Laan, Sander W., Gretarsdottir, Solveig, Anderson, Christopher D., Chong, Michael, Adams, Hieab H. H., Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M., Benavente, Oscar R., Bevan, Steve, Boncoraglio, Giorgio B., Brown, Jr, Robert D., Butterworth, Adam S., Carrera, Caty, Carty, Cara L., Chasman, Daniel I., Chen, Wei-Min, Cole, John W., Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul I. W., DeStefano, Anita L., den Hoed, Marcel, Duan, Qing, Engelter, Stefan T., Falcone, Guido J., Gottesman, Rebecca F., Grewal, Raji P., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B., Hassan, Ahamad, Havulinna, Aki S., Heckbert, Susan R., Holliday, Elizabeth G., Howard, George, Hsu, Fang-Chi, Hyacinth, Hyacinth I., Ikram, M. Arfan, Ingelsson, Erik, Irvin, Marguerite R., Jian, Xueqiu, Jiménez-Conde, Jordi, Johnson, Julie A., Jukema, J. Wouter, Kanai, Masahiro, Keene, Keith L., Kissela, Brett M., Kleindorfer, Dawn O., Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A., Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Lee, Jin-Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M., Lin, Wei-Yu, Lindgren, Arne G., Lorentzen, Erik, Magnusson, Patrik K., Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F., Meschia, James F., Mitchell, Braxton D., Mosley, Thomas H., Nalls, Michael A., Ninomiya, Toshiharu, O’Donnell, Martin J., Psaty, Bruce M., Pulit, Sara L., Rannikmäe, Kristiina, Reiner, Alexander P., Rexrode, Kathryn M., Rice, Kenneth, Rich, Stephen S., Ridker, Paul M., Rost, Natalia S., Rothwell, Peter M., Rotter, Jerome I., Rundek, Tatjana, Sacco, Ralph L., Sakaue, Saori, Sale, Michele M., Salomaa, Veikko, Sapkota, Bishwa R., Schmidt, Reinhold, Schmidt, Carsten O., Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie L. M., Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D., Thijs, Vincent N. S., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, van Duijn, Cornelia M., Walters, Matthew, Wareham, Nicholas J., Wassertheil-Smoller, Sylvia, Wilson, James G., Wiggins, Kerri L., Yang, Qiong, Yusuf, Salim, AFGen Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, International Genomics of Blood Pressure (iGEN-BP) Consortium, INVENT Consortium, STARNET, Bis, Joshua C., Pastinen, Tomi, Ruusalepp, Arno, Schadt, Eric E., Koplev, Simon, Björkegren, Johan L. M., Codoni, Veronica, Civelek, Mete, Smith, Nicholas L., Trégouët, David A., Christophersen, Ingrid E., Roselli, Carolina, Lubitz, Steven A., Ellinor, Patrick T., Tai, E. Shyong, Kooner, Jaspal S., Kato, Norihiro, He, Jiang, van der Harst, Pim, Elliott, Paul, Chambers, John C., Takeuchi, Fumihiko, Johnson, Andrew D., BioBank Japan Cooperative Hospital Group, COMPASS Consortium, EPIC-CVD Consortium, EPIC-InterAct Consortium, International Stroke Genetics Consortium (ISGC), METASTROKE Consortium, Neurology Working Group of the CHARGE Consortium, NINDS Stroke Genetics Network (SiGN), UK Young Lacunar DNA Study, MEGASTROKE Consortium, Sanghera, Dharambir K., Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez-Cadenas, Israel, Longstreth, Jr, W. T., Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C., Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B., Kittner, Steven J., Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S., Howson, Joanna M. M., Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin

Published
2019
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32. Dynamic changes in chromatin accessibility are associated with the atherogenic transitioning of vascular smooth muscle cells

Author

CDL Onderzoek Pasterkamp, Experimentele Afd. Cardiologie 1, Child Health, Circulatory Health, Centraal Diagnostisch Laboratorium, Wang, Ying, Gao, Hua, Wang, Fudi, Ye, Zhongde, Mokry, Michal, Turner, Adam W, Ye, Jianqin, Koplev, Simon, Luo, Lingfeng, Alsaigh, Tom, Adkar, Shaunak S, Elishaev, Maria, Gao, Xiangyu, Maegdefessel, Lars, Björkegren, Johan L M, Pasterkamp, Gerard, Miller, Clint L, Ross, Elsie G, Leeper, Nicholas J, CDL Onderzoek Pasterkamp, Experimentele Afd. Cardiologie 1, Child Health, Circulatory Health, Centraal Diagnostisch Laboratorium, Wang, Ying, Gao, Hua, Wang, Fudi, Ye, Zhongde, Mokry, Michal, Turner, Adam W, Ye, Jianqin, Koplev, Simon, Luo, Lingfeng, Alsaigh, Tom, Adkar, Shaunak S, Elishaev, Maria, Gao, Xiangyu, Maegdefessel, Lars, Björkegren, Johan L M, Pasterkamp, Gerard, Miller, Clint L, Ross, Elsie G, and Leeper, Nicholas J

Published
2022

33. Integrative Prioritization of Causal Genes for Coronary Artery Disease

Author

Hao, Ke, primary, Ermel, Raili, additional, Sukhavasi, Katyayani, additional, Cheng, Haoxiang, additional, Ma, Lijiang, additional, Li, Ling, additional, Amadori, Letizia, additional, Koplev, Simon, additional, Franzén, Oscar, additional, d’Escamard, Valentina, additional, Chandel, Nirupama, additional, Wolhuter, Kathryn, additional, Bryce, Nicole S., additional, Venkata, Vamsidhar R.M., additional, Miller, Clint L., additional, Ruusalepp, Arno, additional, Schunkert, Heribert, additional, Björkegren, Johan L.M., additional, and Kovacic, Jason C., additional

Published
2022
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34. Dynamic changes in chromatin accessibility are associated with the atherogenic transitioning of vascular smooth muscle cells

Author

Wang, Ying, primary, Gao, Hua, additional, Wang, Fudi, additional, Ye, Zhongde, additional, Mokry, Michal, additional, Turner, Adam W, additional, Ye, Jianqin, additional, Koplev, Simon, additional, Luo, Lingfeng, additional, Alsaigh, Tom, additional, Adkar, Shaunak S, additional, Elishaev, Maria, additional, Gao, Xiangyu, additional, Maegdefessel, Lars, additional, Björkegren, Johan L M, additional, Pasterkamp, Gerard, additional, Miller, Clint L, additional, Ross, Elsie G, additional, and Leeper, Nicholas J, additional

Published
2021
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35. Abstract 13468: Single-Cell Driven Drug Repositioning Approach Identifies a New Anti-Atherosclerotic Compound Targeting Myeloid Cells

Author

Amadori, Letizia, primary, Calcagno, Claudia, additional, Fernandez, Dawn M, additional, Koplev, Simon, additional, Fernandez, Nicolas F, additional, Kaur, Ravneet, additional, Shamailova, Roza, additional, Chong, Peik Sean, additional, Sajja, Swathy, additional, Naidu, Sonum, additional, Ghotbi, Adam, additional, Soler, Raphael, additional, Hill, Christopher, additional, Fayad, Zahi A, additional, Ma'ayan, Avi, additional, and Giannarelli, Chiara, additional

Published
2021
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36. Loss of soluble guanylyl cyclase in platelets contributes to atherosclerotic plaque formation and vascular inflammation

Author

Mauersberger, Carina, primary, Sager, Hendrik B, additional, Wobst, Jana, additional, Dang, Tan An, additional, Lambrecht, Laura, additional, Koplev, Simon, additional, Stroth, Marlene, additional, Bettaga, Noomen, additional, Schlossmann, Jens, additional, Wunder, Frank, additional, Friebe, Andreas, additional, Bjoerkegren, Johan LM, additional, Dietz, Lisa, additional, Sandner, Peter, additional, Soehnlein, Oliver, additional, Schunkert, Heribert, additional, and Kessler, Thorsten, additional

Published
2021
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37. Dynamic changes in chromatin accessibility are associated with the atherogenic transitioning of vascular smooth muscle cells.

Author

Wang, Ying, Gao, Hua, Wang, Fudi, Ye, Zhongde, Mokry, Michal, Turner, Adam W, Ye, Jianqin, Koplev, Simon, Luo, Lingfeng, Alsaigh, Tom, Adkar, Shaunak S, Elishaev, Maria, Gao, Xiangyu, Maegdefessel, Lars, Björkegren, Johan L M, Pasterkamp, Gerard, Miller, Clint L, Ross, Elsie G, and Leeper, Nicholas J

Subjects
VASCULAR smooth muscle, MUSCLE cells, COMPUTATIONAL biology, CHROMATIN, TRANSCRIPTION factors, ATHEROSCLEROSIS, EPIGENOMICS
Abstract

Aims De-differentiation and activation of pro-inflammatory pathways are key transitions vascular smooth muscle cells (SMCs) make during atherogenesis. Here, we explored the upstream regulators of this 'atherogenic transition'. Methods and results Genome-wide sequencing studies, including Assay for Transposase-Accessible Chromatin using sequencing and RNA-seq, were performed on cells isolated from both murine SMC-lineage-tracing models of atherosclerosis and human atherosclerotic lesions. At the bulk level, alterations in chromatin accessibility were associated with the atherogenic transitioning of lesional SMCs, especially in relation to genes that govern differentiation status and complement-dependent inflammation. Using computational biology, we observed that a transcription factor previously related to coronary artery disease, Activating transcription factor 3 (ATF3), was predicted to be an upstream regulator of genes altered during the transition. At the single-cell level, our results indicated that ATF3 is a key repressor of SMC transitioning towards the subset of cells that promote vascular inflammation by activating the complement cascade. The expression of ATF3 and complement component C3 was negatively correlated in SMCs from human atherosclerotic lesions, suggesting translational relevance. Phenome-wide association studies indicated that genetic variation that results in reduced expression of ATF3 is correlated with an increased risk for atherosclerosis, and the expression of ATF3 was significantly down-regulated in humans with advanced vascular disease. Conclusion Our study indicates that the plasticity of atherosclerotic SMCs may in part be explained by dynamic changes in their chromatin architecture, which in turn may contribute to their maladaptive response to inflammation-induced stress. [ABSTRACT FROM AUTHOR]

Published
2022
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38. Transcriptome wide association study of coronary artery disease identifies novel susceptibility genes

Author

Schunkert, Heribert, primary, Li, Ling, additional, Chen, Zhifen, additional, Scheidt, Moritz, additional, Steiner, Andrea, additional, Güldener, Ulrich, additional, Koplev, Simon, additional, Ma, Angela, additional, Hao, Ke, additional, Pan, Calvin, additional, Lusis, Aldons, additional, Pang, Shichao, additional, Kessler, Thorsten, additional, Ermel, Raili, additional, Sukhavasi, Katyayani, additional, Ruusalepp, Arno, additional, Gagneur, Julien, additional, Erdmann, Jeanette, additional, Kovacic, Jason, additional, and Bjorkegren, Johan, additional

Published
2021
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39. Transcriptome wide association study of coronary artery disease identifies novel susceptibility genes

Author

Li, Ling, primary, Chen, Zhifen, additional, von Scheidt, Moritz, additional, Steiner, Andrea, additional, Güldener, Ulrich, additional, Koplev, Simon, additional, Ma, Angela, additional, Hao, Ke, additional, Pan, Calvin, additional, Lusis, Aldons J., additional, Pang, Shichao, additional, Kessler, Thorsten, additional, Ermel, Raili, additional, Sukhavasi, Katyayani, additional, Ruusalepp, Arno, additional, Gagneur, Julien, additional, Erdmann, Jeanette, additional, Kovacic, Jason C., additional, Björkegren, Johan L.M., additional, and Schunkert, Heribert, additional

Published
2021
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40. Sex-Stratified Gene Regulatory Networks Reveal Female Key Driver Genes of Atherosclerosis Involved in Smooth Muscle Cell Phenotype Switching

Author

Experimentele Afd. Cardiologie 1, Circulatory Health, CDL Onderzoek Pasterkamp, Onderzoek Precision medicine, Child Health, Onderzoek Vrouw Hart & Vaatziekten, Hartman, Robin J G, Owsiany, Katie, Ma, Lijiang, Koplev, Simon, Hao, Ke, Slenders, Lotte, Civelek, Mete, Mokry, Michal, Kovacic, Jason C, Pasterkamp, Gerard, Owens, Gary, Björkegren, Johan L M, den Ruijter, Hester M, Experimentele Afd. Cardiologie 1, Circulatory Health, CDL Onderzoek Pasterkamp, Onderzoek Precision medicine, Child Health, Onderzoek Vrouw Hart & Vaatziekten, Hartman, Robin J G, Owsiany, Katie, Ma, Lijiang, Koplev, Simon, Hao, Ke, Slenders, Lotte, Civelek, Mete, Mokry, Michal, Kovacic, Jason C, Pasterkamp, Gerard, Owens, Gary, Björkegren, Johan L M, and den Ruijter, Hester M

Published
2021

41. Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade

Author

Electrofysiologie, CDL Onderzoek Pasterkamp, Circulatory Health, Wang, Ying, Nanda, Vivek, Direnzo, Daniel, Ye, Jianqin, Xiao, Sophia, Kojima, Yoko, Howe, Kathryn L., Jarr, Kai Uwe, Flores, Alyssa M., Tsantilas, Pavlos, Tsao, Noah, Rao, Abhiram, Newman, Alexandra A.C., Eberhard, Anne V., Priest, James R., Ruusalepp, Arno, Pasterkamp, Gerard, Maegdefessel, Lars, Miller, Clint L., Lind, Lars, Koplev, Simon, Björkegren, Johan L.M., Owens, Gary K., Ingelsson, Erik, Weissman, Irving L., Leeper, Nicholas J., Electrofysiologie, CDL Onderzoek Pasterkamp, Circulatory Health, Wang, Ying, Nanda, Vivek, Direnzo, Daniel, Ye, Jianqin, Xiao, Sophia, Kojima, Yoko, Howe, Kathryn L., Jarr, Kai Uwe, Flores, Alyssa M., Tsantilas, Pavlos, Tsao, Noah, Rao, Abhiram, Newman, Alexandra A.C., Eberhard, Anne V., Priest, James R., Ruusalepp, Arno, Pasterkamp, Gerard, Maegdefessel, Lars, Miller, Clint L., Lind, Lars, Koplev, Simon, Björkegren, Johan L.M., Owens, Gary K., Ingelsson, Erik, Weissman, Irving L., and Leeper, Nicholas J.

Published
2020

42. Resolving Tumour Clonal Heterogeneity and Spatial Complexity using Nuclear Tandem Epitope Protein (nTEP) Barcoding

Author

Gill, Michael B., Koplev, Simon, Machel, Anne C., and Miller, Martin L.

Subjects
Stromal cell, medicine.anatomical_structure, Immune system, Tumour heterogeneity, biology, Cell culture, Cancer cell, medicine, biology.protein, Computational biology, Complex cell, Antibody, Epitope
Abstract

Tumours are composed of an array of unique cancer cell clones along with many non-tumour cells such as immune cells, fibroblasts and endothelial cells, which make up the complex tumour microenvironment. To better understand the co-evolution of tumour clones and cells of the tumour microenvironment, we require tools to spatially resolve heterotypic cellular interactions at the single cell level. We present a novel protein-based barcoding technology termed nuclear tandem epitope protein (nTEP) barcoding, which can be designed to combinatorially encode and track dozens to hundreds of tumour clones in their spatial context within complex cellular mixtures using multiplexed antibody-based imaging. Here we provide proof-of-principle of nTEP barcoding and develop the technology, which relies on lentiviral - based stable expression of a nuclear-localised fluorophore that contains unique combinations of protein epitope tags that can be decoded by a limited set of antibodies. By generating a series of cell lines expressing unique nTEP barcodes, we were able to robustly identify and spatially deconvolve specific clones present within highly complex cell mixtures at the single cell level using state-of-the-art iterative indirect immunofluorescence imaging (4i). We define the utility of nTEP-barcoding as a powerful tool for visualising and resolving tumour heterogeneity at the cellular level, and envision its usage in mouse tumour models for understanding how tumour clones modulate and interact with stromal- and immune cells in cancer.

Published
2018

43. Systems Pharmacology Identifies an Arterial Wall Regulatory Gene Network Mediating Coronary Artery Disease Side Effects of Antiretroviral Therapy

Author

Frades, Itziar, primary, Readhead, Ben, additional, Amadori, Letizia, additional, Koplev, Simon, additional, Talukdar, Husain A., additional, Crane, Heidi M., additional, Crane, Paul K., additional, Kovacic, Jason C., additional, Dudley, Joel T., additional, Giannarelli, Chiara, additional, Björkegren, Johan L.M., additional, and Peter, Inga, additional

Published
2019
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44. Probability-based detection of phosphoproteomic uncertainty reveals rare signaling events driven by oncogenic kinase gene fusion

Author

Robin, Xavier, primary, Voellmy, Franziska, additional, Ferkinghoff-Borg, Jesper, additional, Howard, Conor, additional, Altenburg, Tom, additional, Engel, Mathias, additional, Simpson, Craig D., additional, Saginc, Gaye, additional, Koplev, Simon, additional, Klipp, Edda, additional, Longden, James, additional, and Linding, Rune, additional

Published
2019
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45. Functional regulatory mechanism of smooth muscle cell-restricted LMOD1 coronary artery disease locus

Author

Nanda, Vivek, primary, Wang, Ting, additional, Pjanic, Milos, additional, Liu, Boxiang, additional, Nguyen, Trieu, additional, Matic, Ljubica Perisic, additional, Hedin, Ulf, additional, Koplev, Simon, additional, Ma, Lijiang, additional, Franzén, Oscar, additional, Ruusalepp, Arno, additional, Schadt, Eric E., additional, Björkegren, Johan L. M., additional, Montgomery, Stephen B., additional, Snyder, Michael P., additional, Quertermous, Thomas, additional, Leeper, Nicholas J., additional, and Miller, Clint L., additional

Published
2018
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47. CD90 Identifies Adventitial Mesenchymal Progenitor Cells in Adult Human Medium- and Large-Sized Arteries

Author

Michelis, Katherine C., primary, Nomura-Kitabayashi, Aya, additional, Lecce, Laura, additional, Franzén, Oscar, additional, Koplev, Simon, additional, Xu, Yang, additional, Santini, Maria Paola, additional, D'Escamard, Valentina, additional, Lee, Jonathan T.L., additional, Fuster, Valentin, additional, Hajjar, Roger, additional, Reddy, Ramachandra C., additional, Chikwe, Joanna, additional, Stelzer, Paul, additional, Filsoufi, Farzan, additional, Stewart, Allan, additional, Anyanwu, Anelechi, additional, Björkegren, Johan L.M., additional, and Kovacic, Jason C., additional

Published
2018
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48. 83 The coronary artery disease associated gene JCAD regulates hippo signalling in endothelial cells

Author

Jones, Peter D, primary, Kaiser, Mike, additional, Najafabadi, Maryam Ghaderi, additional, Andrews, Sarah, additional, Rajmohan, Rathinasabapathy, additional, Ye, Shu, additional, Samani, Nilesh, additional, Webb, Tom, additional, Koplev, Simon, additional, Björkegren, Johan, additional, Zhao, Yuqi, additional, Yang, Xia, additional, Douglas, Gillian, additional, Kyriakou, Theodosios, additional, Watkins, Hugh, additional, and Channon, Keith, additional

Published
2018
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