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CRTC1 gene is differentially methylated in the human hippocampus in Alzheimer’s disease

BACKGROUND: CRTC1 (CREB regulated transcription coactivator 1) gene plays a role in synaptic plasticity, learning and long-term memory formation in the hippocampus. Recently, CRTC1 has been shown to be downregulated in Alzheimer’s disease (AD). Nevertheless, the mechanisms underlying CRTC1 dysregula...

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Autores principales: Mendioroz, Maite, Celarain, Naiara, Altuna, Miren, Sánchez-Ruiz de Gordoa, Javier, Zelaya, María Victoria, Roldán, Miren, Rubio, Idoya, Larumbe, Rosa, Erro, María Elena, Méndez, Iván, Echávarri, Carmen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837517/
https://www.ncbi.nlm.nih.gov/pubmed/27094739
http://dx.doi.org/10.1186/s13195-016-0183-0
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author Mendioroz, Maite
Celarain, Naiara
Altuna, Miren
Sánchez-Ruiz de Gordoa, Javier
Zelaya, María Victoria
Roldán, Miren
Rubio, Idoya
Larumbe, Rosa
Erro, María Elena
Méndez, Iván
Echávarri, Carmen
author_facet Mendioroz, Maite
Celarain, Naiara
Altuna, Miren
Sánchez-Ruiz de Gordoa, Javier
Zelaya, María Victoria
Roldán, Miren
Rubio, Idoya
Larumbe, Rosa
Erro, María Elena
Méndez, Iván
Echávarri, Carmen
author_sort Mendioroz, Maite
collection PubMed
description BACKGROUND: CRTC1 (CREB regulated transcription coactivator 1) gene plays a role in synaptic plasticity, learning and long-term memory formation in the hippocampus. Recently, CRTC1 has been shown to be downregulated in Alzheimer’s disease (AD). Nevertheless, the mechanisms underlying CRTC1 dysregulation in AD remain unclear. METHODS: To understand better the epigenetic mechanisms regulating CRTC1 expression that may be altered in AD, we profiled DNA methylation at CpG site resolution by bisulfite cloning sequencing in two promoter regions (referred to as Prom1 and Prom2) of the CRTC1 gene in human hippocampus from controls and AD cases. Next, we correlated DNA methylation levels with AD-related pathology, i.e., β-amyloid and phosphorylated-tau (p-tau) burden and also measured CRTC1 mRNA levels by RT-qPCR. RESULTS: Methylation levels were lower in AD cases as compared to controls within both promoter regions (Prom1: 0.95 % vs. 5 %, p-value < 0.01 and Prom2: 2.80 % vs. 17.80 %, p-value < 0.001). Interestingly, CRTC1 methylation levels inversely correlated with AD-related neuropathological changes, particularly with p-tau deposition (r(Spearman) = -0.903, p < 0.001). Moreover, a 1.54-fold decrease in CRTC1 mRNA levels was observed in hippocampus of AD cases compared to controls (p < 0.05) supporting the notion that CRTC1 is downregulated in the AD hippocampus. CONCLUSIONS: DNA methylation levels within two distinct promoter regions of the CRTC1 gene were decreased in human hippocampus affected by AD compared with controls and methylation within Prom1 showed a strong inverse correlation with p-tau deposition. Further studies are guaranteed to elucidate the precise role that CRTC1 methylation plays in AD pathophysiology. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13195-016-0183-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-48375172016-04-21 CRTC1 gene is differentially methylated in the human hippocampus in Alzheimer’s disease Mendioroz, Maite Celarain, Naiara Altuna, Miren Sánchez-Ruiz de Gordoa, Javier Zelaya, María Victoria Roldán, Miren Rubio, Idoya Larumbe, Rosa Erro, María Elena Méndez, Iván Echávarri, Carmen Alzheimers Res Ther Research BACKGROUND: CRTC1 (CREB regulated transcription coactivator 1) gene plays a role in synaptic plasticity, learning and long-term memory formation in the hippocampus. Recently, CRTC1 has been shown to be downregulated in Alzheimer’s disease (AD). Nevertheless, the mechanisms underlying CRTC1 dysregulation in AD remain unclear. METHODS: To understand better the epigenetic mechanisms regulating CRTC1 expression that may be altered in AD, we profiled DNA methylation at CpG site resolution by bisulfite cloning sequencing in two promoter regions (referred to as Prom1 and Prom2) of the CRTC1 gene in human hippocampus from controls and AD cases. Next, we correlated DNA methylation levels with AD-related pathology, i.e., β-amyloid and phosphorylated-tau (p-tau) burden and also measured CRTC1 mRNA levels by RT-qPCR. RESULTS: Methylation levels were lower in AD cases as compared to controls within both promoter regions (Prom1: 0.95 % vs. 5 %, p-value < 0.01 and Prom2: 2.80 % vs. 17.80 %, p-value < 0.001). Interestingly, CRTC1 methylation levels inversely correlated with AD-related neuropathological changes, particularly with p-tau deposition (r(Spearman) = -0.903, p < 0.001). Moreover, a 1.54-fold decrease in CRTC1 mRNA levels was observed in hippocampus of AD cases compared to controls (p < 0.05) supporting the notion that CRTC1 is downregulated in the AD hippocampus. CONCLUSIONS: DNA methylation levels within two distinct promoter regions of the CRTC1 gene were decreased in human hippocampus affected by AD compared with controls and methylation within Prom1 showed a strong inverse correlation with p-tau deposition. Further studies are guaranteed to elucidate the precise role that CRTC1 methylation plays in AD pathophysiology. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13195-016-0183-0) contains supplementary material, which is available to authorized users. BioMed Central 2016-04-19 /pmc/articles/PMC4837517/ /pubmed/27094739 http://dx.doi.org/10.1186/s13195-016-0183-0 Text en © Mendioroz et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Mendioroz, Maite
Celarain, Naiara
Altuna, Miren
Sánchez-Ruiz de Gordoa, Javier
Zelaya, María Victoria
Roldán, Miren
Rubio, Idoya
Larumbe, Rosa
Erro, María Elena
Méndez, Iván
Echávarri, Carmen
CRTC1 gene is differentially methylated in the human hippocampus in Alzheimer’s disease
title CRTC1 gene is differentially methylated in the human hippocampus in Alzheimer’s disease
title_full CRTC1 gene is differentially methylated in the human hippocampus in Alzheimer’s disease
title_fullStr CRTC1 gene is differentially methylated in the human hippocampus in Alzheimer’s disease
title_full_unstemmed CRTC1 gene is differentially methylated in the human hippocampus in Alzheimer’s disease
title_short CRTC1 gene is differentially methylated in the human hippocampus in Alzheimer’s disease
title_sort crtc1 gene is differentially methylated in the human hippocampus in alzheimer’s disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837517/
https://www.ncbi.nlm.nih.gov/pubmed/27094739
http://dx.doi.org/10.1186/s13195-016-0183-0
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