Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment

Abstract 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 functi...

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Autores principales:	Elena Muiño, Olga Maisterra, Joan Jiménez-Balado, Natalia Cullell, Caty Carrera, Nuria P. Torres-Aguila, Jara Cárcel-Márquez, Cristina Gallego-Fabrega, Miquel Lledós, Jonathan González-Sánchez, Ferran Olmos-Alpiste, Eva Espejo, Álvaro March, Ramón Pujol, Ana Rodríguez-Campello, Gemma Romeral, Jurek Krupinski, Joan Martí-Fàbregas, Joan Montaner, Jaume Roquer, Israel Fernández-Cadenas
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4a49c263a9844e49ac363edfee1aa85e
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spelling	oai:doaj.org-article:4a49c263a9844e49ac363edfee1aa85e2021-12-02T16:36:12ZGenome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment10.1038/s41598-021-86349-12045-2322https://doaj.org/article/4a49c263a9844e49ac363edfee1aa85e2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86349-1https://doaj.org/toc/2045-2322Abstract 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.Elena MuiñoOlga MaisterraJoan Jiménez-BaladoNatalia CullellCaty CarreraNuria P. Torres-AguilaJara Cárcel-MárquezCristina Gallego-FabregaMiquel LledósJonathan González-SánchezFerran Olmos-AlpisteEva EspejoÁlvaro MarchRamón PujolAna Rodríguez-CampelloGemma RomeralJurek KrupinskiJoan Martí-FàbregasJoan MontanerJaume RoquerIsrael Fernández-CadenasNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Elena Muiño Olga Maisterra Joan Jiménez-Balado Natalia Cullell Caty Carrera Nuria P. Torres-Aguila Jara Cárcel-Márquez Cristina Gallego-Fabrega Miquel Lledós Jonathan González-Sánchez Ferran Olmos-Alpiste Eva Espejo Álvaro March Ramón Pujol Ana Rodríguez-Campello Gemma Romeral Jurek Krupinski Joan Martí-Fàbregas Joan Montaner Jaume Roquer Israel Fernández-Cadenas Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment
description	Abstract 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.
format	article
author	Elena Muiño Olga Maisterra Joan Jiménez-Balado Natalia Cullell Caty Carrera Nuria P. Torres-Aguila Jara Cárcel-Márquez Cristina Gallego-Fabrega Miquel Lledós Jonathan González-Sánchez Ferran Olmos-Alpiste Eva Espejo Álvaro March Ramón Pujol Ana Rodríguez-Campello Gemma Romeral Jurek Krupinski Joan Martí-Fàbregas Joan Montaner Jaume Roquer Israel Fernández-Cadenas
author_facet	Elena Muiño Olga Maisterra Joan Jiménez-Balado Natalia Cullell Caty Carrera Nuria P. Torres-Aguila Jara Cárcel-Márquez Cristina Gallego-Fabrega Miquel Lledós Jonathan González-Sánchez Ferran Olmos-Alpiste Eva Espejo Álvaro March Ramón Pujol Ana Rodríguez-Campello Gemma Romeral Jurek Krupinski Joan Martí-Fàbregas Joan Montaner Jaume Roquer Israel Fernández-Cadenas
author_sort	Elena Muiño
title	Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment
title_short	Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment
title_full	Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment
title_fullStr	Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment
title_full_unstemmed	Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment
title_sort	genome-wide transcriptome study in skin biopsies reveals an association of e2f4 with cadasil and cognitive impairment
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4a49c263a9844e49ac363edfee1aa85e
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Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment

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