RT Journal Article
T1 Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment
A1 Muiño, Elena
A1 Maisterra, Olga
A1 Jiménez-Balado, Joan
A1 Cullell, Natalia
A1 Carrera, Caty
A1 Torres-Aguila, Nuria P.
A1 Cárcel-Márquez, Jara
A1 Gallego-Fabrega, Cristina
A1 Lledós, Miquel
A1 González-Sánchez, Jonathan
A1 Olmos-Alpiste, Ferran
A1 Espejo, Eva
A1 March, Álvaro
A1 Pujol, Ramón
A1 Rodríguez-Campello, Ana
A1 Romeral, Gemma
A1 Krupinski, Jurek
A1 Martí-Fàbregas, Joan
A1 Montaner, Joan
A1 Roquer, Jaume
A1 Fernández-Cadenas, Israel
K1 CADASIL
K1 Gene ontology
K1 Executive function
K1 Transcriptome
K1 mRNA
K1 Endothelial cells
K1 Attention
K1 Mutation
K1 In situ hybridization
K1 Polymerase chain reaction
K1 E2F4 transcription factor
K1 Genome-wide association study
K1 Ontología de genes
K1 Función ejecutiva
K1 Transcriptoma
K1 ARN mensajero
K1 Células endoteliales
K1 Atención
K1 Mutación
K1 Hibridación in situ
K1 Reacción en cadena de la polimerasa
K1 Factor de transcripción E2F4
K1 Estudio de asociación del genoma completo
AB 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.
PB Nature Publishing Group
YR 2021
FD 2021-03-25
LK http://hdl.handle.net/10668/4564
UL http://hdl.handle.net/10668/4564
LA en
NO Muiño E, Maisterra O, Jiménez-Balado J, Cullell N, Carrera C, Torres-Aguila NP, et al. Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment. Sci Rep. 2021 Mar 25;11(1):6846
DS RISalud
RD Apr 11, 2025