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1. Control of spatio-temporal patterning via cell growth in a multicellular synthetic gene circuit

Author

Marco Santorelli, Pranav S. Bhamidipati, Josquin Courte, Benjamin Swedlund, Naisargee Jain, Kyle Poon, Dominik Schildknecht, Andriu Kavanagh, Victoria A. MacKrell, Trusha Sondkar, Mattias Malaguti, Giorgia Quadrato, Sally Lowell, Matt Thomson, and Leonardo Morsut

Subjects
Science
Abstract

Abstract A major goal in synthetic development is to build gene regulatory circuits that control patterning. In natural development, an interplay between mechanical and chemical communication shapes the dynamics of multicellular gene regulatory circuits. For synthetic circuits, how non-genetic properties of the growth environment impact circuit behavior remains poorly explored. Here, we first describe an occurrence of mechano-chemical coupling in synthetic Notch (synNotch) patterning circuits: high cell density decreases synNotch-gated gene expression in different cellular systems in vitro. We then construct, both in vitro and in silico, a synNotch-based signal propagation circuit whose outcome can be regulated by cell density. Spatial and temporal patterning outcomes of this circuit can be predicted and controlled via modulation of cell proliferation, initial cell density, and/or spatial distribution of cell density. Our work demonstrates that synthetic patterning circuit outcome can be controlled via cellular growth, providing a means for programming multicellular circuit patterning outcomes.

Published
2024
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2. GWAS reveals determinants of mobilization rate and dynamics of an active endogenous retrovirus of cattle

Author

Lijing Tang, Benjamin Swedlund, Sébastien Dupont, Chad Harland, Gabriel Costa Monteiro Moreira, Keith Durkin, Maria Artesi, Eric Mullaart, Arnaud Sartelet, Latifa Karim, Wouter Coppieters, Michel Georges, and Carole Charlier

Subjects
Science
Abstract

Abstract Five to ten percent of mammalian genomes is occupied by multiple clades of endogenous retroviruses (ERVs), that may count thousands of members. New ERV clades arise by retroviral infection of the germline followed by expansion by reinfection and/or retrotransposition. ERV mobilization is a source of deleterious variation, driving the emergence of ERV silencing mechanisms, leaving “DNA fossils”. Here we show that the ERVK[2-1-LTR] clade is still active in the bovine and a source of disease-causing alleles. We develop a method to measure the rate of ERVK[2-1-LTR] mobilization, finding an average of 1 per ~150 sperm cells, with >10-fold difference between animals. We perform a genome-wide association study and identify eight loci affecting ERVK[2-1-LTR] mobilization. We provide evidence that polymorphic ERVK[2-1-LTR] elements in four of these loci cause the association. We generate a catalogue of full length ERVK[2-1-LTR] elements, and show that it comprises 15% of C-type autonomous elements, and 85% of D-type non-autonomous elements lacking functional genes. We show that >25% of the variance of mobilization rate is determined by the number of C-type elements, yet that de novo insertions are dominated by D-type elements. We propose that D-type elements act as parasite-of-parasite gene drives that may contribute to the observed demise of ERV elements.

Published
2024
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3. Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis

Author

Françoise Helmbacher, Jose Jf Millan-Cayetano, Ievgenia Pastushenko, L. Ríos-Buceta, Benjamin Swedlund, Alicia Perez-Bustillo, Magdalena De Troya, Delphi Van Haver, Sergio Hassid, Francis Impens, Bob Meeusen, Sophie Lemaire, Yura Song, Christine Decaestecker, Gaëlle Lapouge, Ramon Sieira-Gil, Cédric Balsat, David Perez-Morga, Beatriz Agreda-Moreno, Cédric Blanpain, Pedro Redondo, Matthieu Opitz, Youri Sokolow, Isabelle Salmon, Christos Sotiriou, Onofre Sanmatrtin, Frédérique De Cock, Virginie Moers, Samuel Scozzaro, Marjorie Vermeersch, Pedro Jaén, Yacine Bareche, Christine Dubois, Milena Rozzi, Nicky D'Haene, Manuel Théry, Yves-Remi Van Eycke, Jeremy Blondeau, Veerle Janssens, Federico Mauri, Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium., Dermatology Department, Cliniques de l'Europe, Brussels, Belgium, Université libre de Bruxelles (ULB), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Leuven Cancer Institute (LKI), Leuven, Belgium, VIB-UGent Center for Medical Biotechnology, VIB Proteomics Core, Ghent, Belgium, Universiteit Gent = Ghent University (UGENT), VIB proteomic core, Ghent, Belgium, Alvéole, Paris, France., CytoMorphoLab UMR976 HIPI, CEA, INSERM, Université de Paris, Paris, France, CytoMorphoLab, Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Ecole Polytechnique de Bruxelles, Department of Dermatology, Complejo Asistencial Universitario de León, León, Spain, Department of Otolaryngology - Head and Neck Surgery, Hospital Clinico 'Lozano Blesa', Zaragoza, Spain, Dermatology Department, Ramón y Cajal Hospital, Madrid, Spain, University of Alcalá, Madrid, Spain, Instituto Ramon y Cajal de Investigacion Sanitaria [Madrid, Spain] (IRYCIS), Universidad de Alcalá - University of Alcalá (UAH), Department of Dermatology, Clinica Universidad de Navarra, Navarra, Spain, Department of Maxillofacial Surgery, Head and Neck Surgery, Hospital Clínic, Barcelona, Spain, Department of Dermatology, Hospital Costa del Sol, Marbella, Spain, Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain, Pathology Department, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), WELBIO, Université Libre de Bruxelles (ULB), Brussels, Belgium, Walloon excellence in life sciences and biotechnology (WELBIO), Fonds de la Recherche Scientifique (FNRS), European Regional Development Fund, Walloon Region, Televie (Charity Association), European Research Council, Fond Erasme, Fondation Contre le Cancer, ULB Foundation, Worldwide Cancer Research, Foundation Baillet Latour, Helmbacher, Francoise, Dermatology Department, CHU Brugmann, Université Libre de Bruxelles (ULB), Brussels, Belgium, Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium, VIB Center for Medical Biotechnology, Ghent, Belgium, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium, Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium., Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles (ULB), Charleroi, Belgium, DIAPath, Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles (ULB), Charleroi, Belgium, Laboratory of Image Synthesis and Analysis, Ecole Polytechnique de Bruxelles, Université Libre de Bruxelles (ULB), Brussels, Belgium, Department of Thoracic Surgery, Erasme University Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium, Department of Otolaryngology - Head and Neck Surgery, Erasme University Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium, and Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium

Subjects
0301 basic medicine, Proteomics, Lung Neoplasms, Skin Neoplasms, [SDV]Life Sciences [q-bio], Cell, Metastasis, Mesoderm, Mice, 0302 clinical medicine, Neoplasms, Neoplasm Metastasis, YAP1, Regulation of gene expression, Multidisciplinary, EZH2, Cadherins, 3. Good health, [SDV] Life Sciences [q-bio], Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Hyaluronan Receptors, Phenotype, src-Family Kinases, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Disease Progression, Neoplastic Stem Cells, FAT1, Signal Transduction, Epithelial-Mesenchymal Transition, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, 03 medical and health sciences, SOX2, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Skin Squamous Cell Carcinoma, Animals, Humans, Enhancer of Zeste Homolog 2 Protein, Adaptor Proteins, Signal Transducing, SOXB1 Transcription Factors, Médecine pathologie humaine, Biologie moléculaire, Zinc Finger E-box-Binding Homeobox 1, Epithelial Cells, YAP-Signaling Proteins, medicine.disease, Phosphoproteins, Cancérologie, 030104 developmental biology, Cancer research, Biologie cellulaire, Gene Deletion, Transcription Factors
Abstract

FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers1-5. However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation and progression are poorly understood. Here, using mouse models of skin squamous cell carcinoma and lung tumours, we found that deletion of Fat1 accelerates tumour initiation and malignant progression and promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype. We also found this hybrid EMT state in FAT1-mutated human squamous cell carcinomas. Skin squamous cell carcinomas in which Fat1 was deleted presented increased tumour stemness and spontaneous metastasis. We performed transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies, which revealed that loss of function of FAT1 activates a CAMK2-CD44-SRC axis that promotes YAP1 nuclear translocation and ZEB1 expression that stimulates the mesenchymal state. This loss of function also inactivates EZH2, promoting SOX2 expression, which sustains the epithelial state. Our comprehensive analysis identified drug resistance and vulnerabilities in FAT1-deficient tumours, which have important implications for cancer therapy. Our studies reveal that, in mouse and human squamous cell carcinoma, loss of function of FAT1 promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state., info:eu-repo/semantics/published

Published
2021
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4. Mechanisms of stretch-mediated skin expansion at single-cell resolution

Author

Christine Dubois, Pieter Baatsen, Benjamin Swedlund, Gaëlle Lapouge, Seungmin Han, Benjamin D. Simons, Jens Van Herck, Katlijn Vints, Mariaceleste Aragona, Fadel Tissir, Thierry Voet, Yura Song, Milan Malfait, Alejandro Sifrim, Souhir Gargouri, Sophie Dekoninck, Cédric Blanpain, Malfait, Milan [0000-0001-9144-3701], Song, Yura [0000-0002-1173-9172], Van Herck, Jens [0000-0002-1291-4462], Swedlund, Benjamin [0000-0002-8264-9342], Tissir, Fadel [0000-0002-9292-6622], Simons, Benjamin D [0000-0002-3875-7071], Blanpain, Cédric [0000-0002-4028-4322], Apollo - University of Cambridge Repository, UCL - SSS/IONS - Institute of NeuroScience, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire

Subjects
Transcription, Genetic, Cell, Cell Cycle Proteins, Mechanotransduction, Cellular, Mice, 0302 clinical medicine, Single-cell analysis, Gene Regulatory Networks, RNA-Seq, Mechanotransduction, Cell Self Renewal, Extracellular Signal-Regulated MAP Kinases, Skin, 0303 health sciences, education.field_of_study, Multidisciplinary, integumentary system, Chemistry, Stem Cells, Cell Differentiation, Hydrogels, Adherens Junctions, Chromatin, Cell biology, medicine.anatomical_structure, Stem cell, Single-Cell Analysis, Population, Mice, Transgenic, Article, 03 medical and health sciences, medicine, Animals, RNA, Messenger, Progenitor cell, education, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Mitogen-Activated Protein Kinase Kinases, Epidermis (botany), Base Sequence, Biologie moléculaire, YAP-Signaling Proteins, Chromatin Assembly and Disassembly, Clone Cells, Transcription Factor AP-1, Disease Models, Animal, Mutation, Trans-Activators, Biologie cellulaire, 030217 neurology & neurosurgery
Abstract

The ability of the skin to grow in response to stretching has been exploited in reconstructive surgery1. Although the response of epidermal cells to stretching has been studied in vitro2,3, it remains unclear how mechanical forces affect their behaviour in vivo. Here we develop a mouse model in which the consequences of stretching on skin epidermis can be studied at single-cell resolution. Using a multidisciplinary approach that combines clonal analysis with quantitative modelling and single-cell RNA sequencing, we show that stretching induces skin expansion by creating a transient bias in the renewal activity of epidermal stem cells, while a second subpopulation of basal progenitors remains committed to differentiation. Transcriptional and chromatin profiling identifies how cell states and gene-regulatory networks are modulated by stretching. Using pharmacological inhibitors and mouse mutants, we define the step-by-step mechanisms that control stretch-mediated tissue expansion at single-cell resolution in vivo. Single-cell analysis in a mouse model of skin stretching shows that stretching causes a transient expansion bias in a population of epidermal stem cells, which is associated with chromatin remodelling and changes in transcriptional profiles.

Published
2020

5. Epidermal autonomous VEGFA/Flt1/Nrp1 functions mediate psoriasis-like disease

Author

Cédric Blanpain, Farida Benhadou, Audrey Brisebarre, Benjamin Swedlund, Yura Song, Maria Sibilia, Elisabeth Glitzner, Christine Dubois, Milena Rozzi, Véronique Del Marmol, and Catherine Paulissen

Subjects
Keratinocytes, Vascular Endothelial Growth Factor A, endocrine system, Transcription, Genetic, Angiogenesis, JUNB, Diseases and Disorders, Biology, Chromatin remodeling, 03 medical and health sciences, 0302 clinical medicine, Psoriasis, medicine, Animals, Antibodies, Blocking, Research Articles, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Multidisciplinary, Vascular Endothelial Growth Factor Receptor-1, SciAdv r-articles, Cell Biology, FOSL1, Sciences bio-médicales et agricoles, medicine.disease, Chromatin Assembly and Disassembly, Neuropilin-1, 3. Good health, Chromatin, Vascular endothelial growth factor A, medicine.anatomical_structure, Phenotype, Epidermal Cells, Cancer research, Keratinocyte, Proto-Oncogene Proteins c-fos, 030215 immunology, Signal Transduction, Transcription Factors, Research Article
Abstract

Vefga induces psoriasis by acting on keratinocytes through Flt1 and Nrp1 receptors., Psoriasis is a common chronic skin disorder characterized by keratinocyte hyperproliferation with altered differentiation accompanied by inflammation and increased angiogenesis. It remains unclear whether the first events that initiate psoriasis development occur in keratinocytes or inflammatory cells. Here, using different psoriasis mouse models, we showed that conditional deletion of Flt1 or Nrp1 in epidermal cells inhibited psoriasis mediated by Vegfa overexpression or c-Jun/JunB deletion. Administration of anti-Nrp1 antibody reverted the psoriasis phenotype. Using transcriptional and chromatin profiling of epidermal cells following Vegfa overexpression together with Flt1 or Nrp1 deletion, we identified the gene regulatory network regulated by Vegfa/Nrp1/Flt1 during psoriasis development and uncovered a key role of Fosl1 in regulating the chromatin remodeling mediated by Vegfa overexpression in keratinocytes. In conclusion, our study identifies an epidermal autonomous function of Vegfa/Nrp1/Flt1 that mediates psoriatic-like disease and demonstrates the clinical relevance of blocking Vegfa/Nrp1/Flt1 axis in psoriasis.

Published
2020

6. Cardiopharyngeal progenitor specification: multiple roads to the heart and head muscles

Author

Fabienne Lescroart, Benjamin Swedlund, Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium., Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and lescroart, fabienne

Subjects
Génétique du développement, Cell type, Lineage (genetic), [SDV]Life Sciences [q-bio], Population, Embryonic Development, Biology, General Biochemistry, Genetics and Molecular Biology, Mesoderm, 03 medical and health sciences, 0302 clinical medicine, Single-cell analysis, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Basic Helix-Loop-Helix Transcription Factors, Animals, Humans, Cell Lineage, Progenitor cell, Muscle, Skeletal, education, [SDV.BDD]Life Sciences [q-bio]/Development Biology, 030304 developmental biology, Progenitor, 0303 health sciences, education.field_of_study, Heart development, Stem Cells, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Gene Expression Regulation, Developmental, Neural crest, Cell Differentiation, Heart, Sciences bio-médicales et agricoles, [SDV] Life Sciences [q-bio], [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, PERSPECTIVES, Neural Crest, embryonic structures, Single-Cell Analysis, Biologie, Head, Neuroscience, 030217 neurology & neurosurgery, Signal Transduction
Abstract

International audience; During embryonic development, the heartarise from various sourcesof undifferentiated mesodermal progenitors, with an additional contribution from ectodermal neural crest cells. Mesodermal cardiac progenitorsareplasticand multipotent,but are nevertheless specified to a precise heart region and cell type very early during development. Recent findings have defined both this lineage plasticity and early commitment of cardiac progenitors, using a combination of single-cell and population analyses. In this review, we discuss several aspects of cardiac progenitor specification. We discuss their markers, fate potential in vitroand in vivo, early segregation and commitment, and also intrinsic and extrinsic cues regulatinglineage restrictionfrom multipotency to a specific cell type of the heart. Finally, we also discuss the sub-divisionsof the cardiopharyngeal field, and the shared origins of the heart with other mesodermal derivatives, including head and neck muscles.

Published
2019

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