Downloads provided by UsageCountsGenome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment
Copyright policy ) Muiño, E; Maisterra, O; Jiménez-Balado, J; Cullell, N; Carrera, C; Torres-Aguila, NP; Cárcel-Márquez, J; +14 Authors
Muiño, E; Maisterra, O; Jiménez-Balado, J; Cullell, N; Carrera, C; Torres-Aguila, NP; Cárcel-Márquez, J; Gallego-Fabrega, C; Lledós, M; González-Sánchez, J; Olmos-Alpiste, F; Espejo, E; March, Á; Pujol, R; Rodríguez-Campello, A; Romeral, G; Krupinski, J; Martí-Fàbregas, J; Montaner, J; Roquer, J; Fernández-Cadenas, I;
Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment
AbstractCADASIL is a small vessel disease caused by mutations inNOTCH3that 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 × 10–4andPDCD6IP,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 × 10–3andE2F4,p-value = 4.77 × 10–3) due to their association with ischemic neuronal death.E2F4showed 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, higherE2F4expression 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 showedE2F4expression in endothelial and vascular smooth vessel cells. In silico studies indicated thatE2F4is 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.
Spain, United Kingdom, Spain
- University of St Andrews United Kingdom
- Spanish National Research Council Spain
- Hospital Universitario Virgen del Rocío Spain
- Autonomous University of Barcelona Spain
- University of Seville Spain
Male, FENÓMENOS Y PROCESOS::fenómenos genéticos::expresión génica::transcripción genética::fenómenos genéticos::transcriptoma, QH301 Biology, Biopsy, PATHOGENESIS, Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies, Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Nucleic Acid Amplification Techniques::Polymerase Chain Reaction, CADASIL, Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans, Transcriptomes, Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Transcription, Genetic::Transcriptome, PSIQUIATRÍA Y PSICOLOGÍA::trastornos mentales::trastornos neurocognitivos::trastornos cognitivos::disfunción cognitiva, NOTCH3, Medical Subject Headings::Anatomy::Integumentary System::Skin, Medical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Adhesion, Medical Subject Headings::Diseases::Cardiovascular Diseases::Vascular Diseases::Cerebrovascular Disorders::Cerebral Small Vessel Diseases::CADASIL, Medical Subject Headings::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, Skin, Q, R, Headache, PHENOMENA AND PROCESSES::Genetic Phenomena::Gene Expression::Transcription, Genetic::Genetic Phenomena::Transcriptome, MUSCLE, Medical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Receptor Aggregation, Middle Aged, Multidisciplinary Sciences, Medical Subject Headings::Check Tags::Male, Stroke, Medical Subject Headings::Anatomy::Musculoskeletal System::Muscles::Muscle, Smooth::Muscle, Smooth, Vascular, NEURONORMA PROJECT NORMS, Otros calificadores::Otros calificadores::Otros calificadores::/patología, Science & Technology - Other Topics, Medicine, Medical Subject Headings::Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genetic Research::Gene Ontology, Female, VASOREACTIVITY, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Medical Subject Headings::Persons::Persons::Age Groups::Adult, EXPRESSION, Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies::Genome-Wide Association Study, Adult, Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome, Human, Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation, Medical Subject Headings::Anatomy::Cells::Epithelial Cells::Endothelial Cells, PROTEINS, Science, NDAS, 610, Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors::E2F Transcription Factors::E2F4 Transcription Factor, Medical Subject Headings::Diseases::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Headache Disorders::Headache Disorders, Primary::Migraine Disorders, QH426 Genetics, E2F4 Transcription Factor, Medical Subject Headings::Anatomy::Nervous System::Central Nervous System::Brain, Trastorns de la cognició, Article, PSYCHIATRY AND PSYCHOLOGY::Mental Disorders::Neurocognitive Disorders::Cognition Disorders::Cognitive Dysfunction, QH301, Medical Subject Headings::Persons::Persons::Age Groups::Adult::Middle Aged, Humans, Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Cytodiagnosis::Biopsy, Cognitive Dysfunction, Medical Subject Headings::Psychiatry and Psychology::Psychological Phenomena and Processes::Psychophysiology::Arousal::Attention, QH426, Other subheadings::Other subheadings::Other subheadings::/pathology, Science & Technology, Genome, Human, Medical Subject Headings::Check Tags::Female, Medical Subject Headings::Psychiatry and Psychology::Psychological Phenomena and Processes::Mental Processes::Executive Function, Medical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Messenger, Case-Control Studies, Mutation, RC0321, Dementia, Transcriptome, Genome-Wide Association Study
Male, FENÓMENOS Y PROCESOS::fenómenos genéticos::expresión génica::transcripción genética::fenómenos genéticos::transcriptoma, QH301 Biology, Biopsy, PATHOGENESIS, Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies, Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Nucleic Acid Amplification Techniques::Polymerase Chain Reaction, CADASIL, Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans, Transcriptomes, Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Transcription, Genetic::Transcriptome, PSIQUIATRÍA Y PSICOLOGÍA::trastornos mentales::trastornos neurocognitivos::trastornos cognitivos::disfunción cognitiva, NOTCH3, Medical Subject Headings::Anatomy::Integumentary System::Skin, Medical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Adhesion, Medical Subject Headings::Diseases::Cardiovascular Diseases::Vascular Diseases::Cerebrovascular Disorders::Cerebral Small Vessel Diseases::CADASIL, Medical Subject Headings::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, Skin, Q, R, Headache, PHENOMENA AND PROCESSES::Genetic Phenomena::Gene Expression::Transcription, Genetic::Genetic Phenomena::Transcriptome, MUSCLE, Medical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Receptor Aggregation, Middle Aged, Multidisciplinary Sciences, Medical Subject Headings::Check Tags::Male, Stroke, Medical Subject Headings::Anatomy::Musculoskeletal System::Muscles::Muscle, Smooth::Muscle, Smooth, Vascular, NEURONORMA PROJECT NORMS, Otros calificadores::Otros calificadores::Otros calificadores::/patología, Science & Technology - Other Topics, Medicine, Medical Subject Headings::Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genetic Research::Gene Ontology, Female, VASOREACTIVITY, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Medical Subject Headings::Persons::Persons::Age Groups::Adult, EXPRESSION, Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies::Genome-Wide Association Study, Adult, Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome, Human, Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation, Medical Subject Headings::Anatomy::Cells::Epithelial Cells::Endothelial Cells, PROTEINS, Science, NDAS, 610, Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors::E2F Transcription Factors::E2F4 Transcription Factor, Medical Subject Headings::Diseases::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Headache Disorders::Headache Disorders, Primary::Migraine Disorders, QH426 Genetics, E2F4 Transcription Factor, Medical Subject Headings::Anatomy::Nervous System::Central Nervous System::Brain, Trastorns de la cognició, Article, PSYCHIATRY AND PSYCHOLOGY::Mental Disorders::Neurocognitive Disorders::Cognition Disorders::Cognitive Dysfunction, QH301, Medical Subject Headings::Persons::Persons::Age Groups::Adult::Middle Aged, Humans, Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Cytodiagnosis::Biopsy, Cognitive Dysfunction, Medical Subject Headings::Psychiatry and Psychology::Psychological Phenomena and Processes::Psychophysiology::Arousal::Attention, QH426, Other subheadings::Other subheadings::Other subheadings::/pathology, Science & Technology, Genome, Human, Medical Subject Headings::Check Tags::Female, Medical Subject Headings::Psychiatry and Psychology::Psychological Phenomena and Processes::Mental Processes::Executive Function, Medical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Messenger, Case-Control Studies, Mutation, RC0321, Dementia, Transcriptome, Genome-Wide Association Study
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