Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment
Por:
Muino, E, Maisterra, O, Jimenez-Balado, J, Cullell, N, Carrera, C, Torres-Aguila, NP, Carcel-Marquez, J, Gallego-Fabrega, C, Lledos, M, Gonzalez-Sanchez, J, Olmos-Alpiste, F, Espejo, E, March, A, Pujol, R, Rodriguez-Campello, A, Romeral, G, Krupinski, J, Marti-Fabregas, J, Montaner, J, Roquer, J, Fernandez-Cadenas, I
Publicada:
25 mar 2021
Resumen:
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=7.23x10(-4) and PDCD6IP, p-value=8.36x10(-4)) were selected for the validation study by qRT-PCR. Additionally, we selected two more mRNAs (CAMK2G, p-value=4.52x10(-3) and E2F4, p-value=4.77x10(-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=1.23x10(-3)), and it was upregulated in CADASIL cases. Furthermore, higher E2F4 expression was associated with worse executive function (p=2.04x10(-2)) and attention and information processing speed (IPS) (p=8.73x10(-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.
Filiaciones:
Muino, E:
Hosp Santa Creu & Sant Pau, Stroke Pharmacogen & Genet Grp, Inst Recerca, C St Antoni Maria Claret 167, Barcelona, Spain
Maisterra, O:
Univ Autonoma Barcelona, Hosp Vall dHebron, Vall dHebron Inst Res, Neurovasc Res Lab, Barcelona, Spain
Jimenez-Balado, J:
Univ Autonoma Barcelona, Hosp Vall dHebron, Vall dHebron Inst Res, Neurovasc Res Lab, Barcelona, Spain
Cullell, N:
Hosp Santa Creu & Sant Pau, Stroke Pharmacogen & Genet Grp, Inst Recerca, C St Antoni Maria Claret 167, Barcelona, Spain
Fundacio MutuaTerrassa Docencia & Recerca, Stroke Pharmacogen & Genet, Terrassa, Spain
Carrera, C:
Hosp Santa Creu & Sant Pau, Stroke Pharmacogen & Genet Grp, Inst Recerca, C St Antoni Maria Claret 167, Barcelona, Spain
Torres-Aguila, NP:
Hosp Santa Creu & Sant Pau, Stroke Pharmacogen & Genet Grp, Inst Recerca, C St Antoni Maria Claret 167, Barcelona, Spain
Carcel-Marquez, J:
Hosp Santa Creu & Sant Pau, Stroke Pharmacogen & Genet Grp, Inst Recerca, C St Antoni Maria Claret 167, Barcelona, Spain
Gallego-Fabrega, C:
Hosp Santa Creu & Sant Pau, Stroke Pharmacogen & Genet Grp, Inst Recerca, C St Antoni Maria Claret 167, Barcelona, Spain
Fundacio MutuaTerrassa Docencia & Recerca, Stroke Pharmacogen & Genet, Terrassa, Spain
Lledos, M:
Hosp Santa Creu & Sant Pau, Stroke Pharmacogen & Genet Grp, Inst Recerca, C St Antoni Maria Claret 167, Barcelona, Spain
Gonzalez-Sanchez, J:
Fundacio MutuaTerrassa Docencia & Recerca, Stroke Pharmacogen & Genet, Terrassa, Spain
Manchester Metropolitan Univ All St, Manchester, Lancs, England
Olmos-Alpiste, F:
Hosp Mar Parc Salut Mar, Dermatol Dept, Barcelona, Spain
Espejo, E:
Hosp Mar Parc Salut Mar, Dermatol Dept, Barcelona, Spain
March, A:
Hosp Mar Parc Salut Mar, Dermatol Dept, Barcelona, Spain
Pujol, R:
Hosp Mar Parc Salut Mar, Dermatol Dept, Barcelona, Spain
Rodriguez-Campello, A:
IMIM Hosp del Mar, Neurol Dept, Barcelona, Spain
Romeral, G:
IMIM Hosp del Mar, Neurol Dept, Barcelona, Spain
Krupinski, J:
Hosp Mutua Terrassa, Neurol Dept, Terrassa, Spain
Marti-Fabregas, J:
Hosp Santa Creu & Sant Pau, Biomed Res Inst St Pau IIB St Pau, Neurol Dept, Barcelona, Spain
Montaner, J:
Manchester Metropolitan Univ All St, Manchester, Lancs, England
Univ Seville, IBiS Hosp Univ Virgen del Rocio CSIC, Biomed Inst Seville, Seville, Spain
Hosp Univ Virgen Macarena, Dept Neurol, Seville, Spain
Roquer, J:
IMIM Hosp del Mar, Neurol Dept, Barcelona, Spain
Fernandez-Cadenas, I:
Hosp Santa Creu & Sant Pau, Stroke Pharmacogen & Genet Grp, Inst Recerca, C St Antoni Maria Claret 167, Barcelona, Spain
Green Published, Green Submitted, gold
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