Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment
| Autor: | Israel Fernandez-Cadenas, Miquel Lledós, Ramon M. Pujol, Natalia Cullell, Jara Cárcel-Márquez, Olga Maisterra, Elena Muiño, Joan Jiménez-Balado, Cristina Gallego-Fabrega, Joan Montaner, Gemma Romeral, Jurek Krupinski, Ferran Olmos-Alpiste, Ana Rodríguez-Campello, Álvaro March, Eva Espejo, Jonathan González-Sánchez, Jaume Roquer, Caty Carrera, Nuria P. Torres-Aguila, Joan Martí-Fàbregas |
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| Přispěvatelé: | University of St Andrews. School of Biology, [Muiño,E, Cullell,N, Carrera,C, Torres-Aguila,NP, Cárcel-Márquez,J, Gallego-Fabrega,C, Lledós,M, Fernández-Cadenas,I] Stroke Pharmacogenomics and Genetics Group, Institut de Recerca de l`Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. [Maisterra,O, Jiménez-Balado,J] Neurovascular Research Laboratory, Vall d’Hebron Institute of Research, Hospital Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. [Gallego-Fabrega,C, González-Sánchez,J] Stroke Pharmacogenomics and Genetics, Fundació MútuaTerrassa per la Docència i la Recerca, Terrassa, Spain. [González-Sánchez,J] The Manchester Metropolitan University of All Saints, Manchester, UK. [Olmos-Alpiste,F, Espejo,E, March,A, Pujol,R] Dermatology Department, Hospital del Mar-Parc de Salut Mar, Barcelona, Spain. [Rodríguez-Campello,A, Romeral,G, Roquer,J] Neurology Department, IMIM-Hospital del Mar, Barcelona, Spain. [Krupinski,J] Neurology Department, Hospital Mútua Terrassa, Terrassa, Spain. [Martí-Fàbregas,J] Neurology Department, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain. [Montaner,J] Biomedicine Institute of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC, University of Seville, Seville, Spain. [Montaner,J] Department of Neurology, Hospital Universitario Virgen Macarena, Seville, Spain, This work was supported by a grant from the Carlos III Health Institute (PI 11/0176), Generación Project, Maestro Project, INVICTUS + network, Epigenesis Project (Marató de TV3), FEDER funds and economic donations from 'Asociación CADASIL España'. E. Muiño is supported by a Río Hortega Contract (CM18/00198) from the Carlos III Health Institute. J. Cárcel-Márquez is supported by an AGAUR Contract (agència de gestió d'ajuts universitaris i de recerca, FI_DGR 2019, grant number 2019_FI_B 00853) co-financed with Fons Social Europeu (FSE). M. Lledós is supported by a PFIS Contract (Contratos Predoctorales de Formación en Investigación en Salud) from the Carlos III Health Institute., Instituto de Salud Carlos III, Fundació La Marató de TV3, European Commission, Cadasil, Agència de Gestió d'Ajuts Universitaris i de Recerca, Institut Català de la Salut, [Muiño E, Carrera C, Torres-Aguila NP] Stroke Pharmacogenomics and Genetics Group, Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. [Maisterra O, Jiménez-Balado J] Laboratori de Recerca Neurovascular, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Cullell N] Stroke Pharmacogenomics and Genetics Group, Institut de Recerca de l`Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Stroke Pharmacogenomics and Genetics, Fundació MútuaTerrassa per la Docència i la Recerca, Terrassa, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Rok vydání: | 2021 |
| Předmět: |
Atención
Male Pathology Endothelial cells Ontología de genes Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genetic Research::Gene Ontology [Medical Subject Headings] Biopsy QH301 Biology Estudio de asociación del genoma completo CADASIL Transcriptomes Chemicals and Drugs::Amino Acids Peptides and Proteins::Proteins::Transcription Factors::E2F Transcription Factors::E2F4 Transcription Factor [Medical Subject Headings] Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] Transcriptome Diseases::Cardiovascular Diseases::Vascular Diseases::Cerebrovascular Disorders::Cerebral Small Vessel Diseases::CADASIL [Medical Subject Headings] Anatomy::Musculoskeletal System::Muscles::Muscle Smooth::Muscle Smooth Vascular [Medical Subject Headings] Reacción en cadena de la polimerasa Anatomy::Cells::Epithelial Cells::Endothelial Cells [Medical Subject Headings] Attention Diseases::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Headache Disorders::Headache Disorders Primary::Migraine Disorders [Medical Subject Headings] E2F4 Skin Multidisciplinary Analytical Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies [Medical Subject Headings] medicine.diagnostic_test Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Adhesion [Medical Subject Headings] Headache Middle Aged Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Human [Medical Subject Headings] Polymerase chain reaction Anatomy::Integumentary System::Skin [Medical Subject Headings] Stroke Other subheadings::Other subheadings::/pathology [Other subheadings] Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Receptor Aggregation [Medical Subject Headings] Medicine Biomarker (medicine) Female Otros calificadores::Otros calificadores::/patología [Otros calificadores] Hibridación in situ fenómenos genéticos::expresión génica::transcripción genética::fenómenos genéticos::transcriptoma [FENÓMENOS Y PROCESOS] In situ hybridization RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry trastornos mentales::trastornos neurocognitivos::trastornos cognitivos::disfunción cognitiva [PSIQUIATRÍA Y PSICOLOGÍA] Adult medicine.medical_specialty Cell type Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation [Medical Subject Headings] mRNA Science In silico NDAS Check Tags::Male [Medical Subject Headings] E2F4 Transcription Factor QH426 Genetics Biology Trastorns de la cognició Article Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Transcription Genetic::Transcriptome [Medical Subject Headings] QH301 Executive function Psychiatry and Psychology::Psychological Phenomena and Processes::Psychophysiology::Arousal::Attention [Medical Subject Headings] Analytical Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Cytodiagnosis::Biopsy [Medical Subject Headings] medicine Humans Cognitive Dysfunction Analytical Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Histocytological Preparation Techniques::Staining and Labeling::In Situ Hybridization [Medical Subject Headings] Función ejecutiva Persons::Persons::Age Groups::Adult [Medical Subject Headings] QH426 Mutación ARN mensajero Genome Human Analytical Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies::Genome-Wide Association Study [Medical Subject Headings] Factor de transcripción E2F4 Genetic Phenomena::Gene Expression::Transcription Genetic::Genetic Phenomena::Transcriptome [PHENOMENA AND PROCESSES] Células endoteliales Analytical Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Nucleic Acid Amplification Techniques::Polymerase Chain Reaction [Medical Subject Headings] Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings] Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings] Chemicals and Drugs::Nucleic Acids Nucleotides and Nucleosides::Nucleic Acids::RNA::RNA Messenger [Medical Subject Headings] medicine.disease Transcriptoma Check Tags::Female [Medical Subject Headings] Case-Control Studies Mental Disorders::Neurocognitive Disorders::Cognition Disorders::Cognitive Dysfunction [PSYCHIATRY AND PSYCHOLOGY] Mutation Skin biopsy Psychiatry and Psychology::Psychological Phenomena and Processes::Mental Processes::Executive Function [Medical Subject Headings] RC0321 Gene ontology Dementia Genome-Wide Association Study |
| Zdroj: | Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona Scientific Reports, Vol 11, Iss 1, Pp 1-12 (2021) Digital.CSIC. Repositorio Institucional del CSIC instname Scientific Reports r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau Scientia |
| ISSN: | 2045-2322 |
| Popis: | CADASIL is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the EGF-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraine, psychiatric disturbances, recurrent strokes and dementia, being executive function characteristically impaired. The molecular pathways altered by this receptor aggregation need to be studied further. A genome-wide transcriptome study (four cases paired with three healthy siblings) was carried out, in addition to a qRT-PCR for validation purposes (ten new cases and eight new controls). To study the expression profile by cell type of the significant mRNAs found, we performed an in situ hybridization (ISH) (nine cases and eight controls) and a research in the Single-nuclei Brain RNA-seq expression browser (SNBREB). Pathway analysis enrichment was carried out with Gene Ontology and Reactome. Neuropsychological tests were performed in five of the qRT-PCR cases. The two most significant differentially expressed mRNAs (BANP, p-value = 7.23 × 10–4 and PDCD6IP, p-value = 8.36 × 10–4) were selected for the validation study by qRT-PCR. Additionally, we selected two more mRNAs (CAMK2G, p-value = 4.52 × 10–3 and E2F4, p-value = 4.77 × 10–3) due to their association with ischemic neuronal death. E2F4 showed differential expression in the genome-wide transcriptome study and in the qRT-PCR (p = 1.23 × 10–3), and it was upregulated in CADASIL cases. Furthermore, higher E2F4 expression was associated with worse executive function (p = 2.04 × 10–2) and attention and information processing speed (IPS) (p = 8.73 × 10–2). In situ hibridization showed E2F4 expression in endothelial and vascular smooth vessel cells. In silico studies indicated that E2F4 is also expressed in brain endothelial cells. Among the most significant pathways analyzed, there was an enrichment of vascular development, cell adhesion and vesicular machinery terms and autophagy process. E2F4 is more highly expressed in the skin biopsy of CADASIL patients compared to controls, and its expression is present in endothelial cells and VSMCs. Further studies are needed to understand whether E2F4 could be useful as a biomarker, to monitor the disease or be used as a therapeutic target. This work was supported by a grant from the Carlos III Health Institute (PI 11/0176), Generación Project, Maestro Project, INVICTUS + network, Epigenesis Project (Marató de TV3), FEDER funds and economic donations from “Asociación CADASIL España”. E. Muiño is supported by a Río Hortega Contract (CM18/00198) from the Carlos III Health Institute. J. Cárcel-Márquez is supported by an AGAUR Contract (agència de gestió d'ajuts universitaris i de recerca; FI_DGR 2019, grant number 2019_FI_B 00853) co-financed with Fons Social Europeu (FSE). M. Lledós is supported by a PFIS Contract (Contratos Predoctorales de Formación en Investigación en Salud) from the Carlos III Health Institute. |
| Databáze: | OpenAIRE |
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