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Gene expression network analysis reveals new transcriptional regulators as novel factors in human ischemic cardiomyopathy

BACKGROUND: Ischemic cardiomyopathy (ICM) is characterized by transcriptomic changes that alter cellular processes leading to decreased cardiac output. Because the molecular network of ICM is largely unknown, the aim of this study was to characterize the role of new transcriptional regulators in the...

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Autores principales: Herrer, Isabel, Roselló-Lletí, Esther, Ortega, Ana, Tarazón, Estefanía, Molina-Navarro, María Micaela, Triviño, Juan Carlos, Martínez-Dolz, Luis, Almenar, Luis, Lago, Francisca, Sánchez-Lázaro, Ignacio, González-Juanatey, José Ramón, Salvador, Antonio, Portolés, Manuel, Rivera, Miguel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386080/
https://www.ncbi.nlm.nih.gov/pubmed/25884818
http://dx.doi.org/10.1186/s12920-015-0088-y
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author Herrer, Isabel
Roselló-Lletí, Esther
Ortega, Ana
Tarazón, Estefanía
Molina-Navarro, María Micaela
Triviño, Juan Carlos
Martínez-Dolz, Luis
Almenar, Luis
Lago, Francisca
Sánchez-Lázaro, Ignacio
González-Juanatey, José Ramón
Salvador, Antonio
Portolés, Manuel
Rivera, Miguel
author_facet Herrer, Isabel
Roselló-Lletí, Esther
Ortega, Ana
Tarazón, Estefanía
Molina-Navarro, María Micaela
Triviño, Juan Carlos
Martínez-Dolz, Luis
Almenar, Luis
Lago, Francisca
Sánchez-Lázaro, Ignacio
González-Juanatey, José Ramón
Salvador, Antonio
Portolés, Manuel
Rivera, Miguel
author_sort Herrer, Isabel
collection PubMed
description BACKGROUND: Ischemic cardiomyopathy (ICM) is characterized by transcriptomic changes that alter cellular processes leading to decreased cardiac output. Because the molecular network of ICM is largely unknown, the aim of this study was to characterize the role of new transcriptional regulators in the molecular mechanisms underlying the responses to ischemia. METHODS: Myocardial tissue explants from ICM patients and control (CNT) subjects were analyzed by RNA-Sequencing (RNA-Seq) and quantitative Real-Time PCR. RESULTS: Enrichment analysis of the ICM transcriptomic profile allowed the characterization of novel master regulators. We found that the expression of the transcriptional regulators SP100 (−1.5-fold, p < 0.05), CITED2 (−3.8-fold, p < 0.05), CEBPD (−4.9-fold, p < 0.05) and BCL3 (−3.3-fold, p < 0.05) were lower in ICM than in CNT. To gain insights into the molecular network defined by the transcription factors, we identified CEBPD, BCL3, and HIF1A target genes in the RNA-Seq datasets. We further characterized the biological processes of the target genes by gene ontology annotation. Our results suggest that CEBPD-inducible genes with roles in the inhibition of apoptosis are downregulated and that BCL3-repressible genes are involved in the regulation of cellular metabolism in ICM. Moreover, our results suggest that CITED2 downregulation causes increased expression of HIF1A target genes. Functional analysis of HIF1A target genes revealed that hypoxic and stress response genes are activated in ICM. Finally, we found a significant correlation between the mRNA levels of BCL3 and the mRNA levels of both CEBPD (r = 0.73, p < 0.001) and CITED2 (r = 0.56, p < 0.05). Interestingly, CITED2 mRNA levels are directly related to ejection fraction (EF) (r = 0.54, p < 0.05). CONCLUSIONS: Our data indicate that changes in the expression of SP100, CITED2, CEBPD, and BCL3 affect their transcription regulatory networks, which subsequently alter a number of biological processes in ICM patients. The relationship between CITED2 mRNA levels and EF emphasizes the importance of this transcription factor in ICM. Moreover, our findings identify new mechanisms used to interpret gene expression changes in ICM and provide valuable resources for further investigation of the molecular basis of human cardiac ischemic response. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12920-015-0088-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-43860802015-04-07 Gene expression network analysis reveals new transcriptional regulators as novel factors in human ischemic cardiomyopathy Herrer, Isabel Roselló-Lletí, Esther Ortega, Ana Tarazón, Estefanía Molina-Navarro, María Micaela Triviño, Juan Carlos Martínez-Dolz, Luis Almenar, Luis Lago, Francisca Sánchez-Lázaro, Ignacio González-Juanatey, José Ramón Salvador, Antonio Portolés, Manuel Rivera, Miguel BMC Med Genomics Research Article BACKGROUND: Ischemic cardiomyopathy (ICM) is characterized by transcriptomic changes that alter cellular processes leading to decreased cardiac output. Because the molecular network of ICM is largely unknown, the aim of this study was to characterize the role of new transcriptional regulators in the molecular mechanisms underlying the responses to ischemia. METHODS: Myocardial tissue explants from ICM patients and control (CNT) subjects were analyzed by RNA-Sequencing (RNA-Seq) and quantitative Real-Time PCR. RESULTS: Enrichment analysis of the ICM transcriptomic profile allowed the characterization of novel master regulators. We found that the expression of the transcriptional regulators SP100 (−1.5-fold, p < 0.05), CITED2 (−3.8-fold, p < 0.05), CEBPD (−4.9-fold, p < 0.05) and BCL3 (−3.3-fold, p < 0.05) were lower in ICM than in CNT. To gain insights into the molecular network defined by the transcription factors, we identified CEBPD, BCL3, and HIF1A target genes in the RNA-Seq datasets. We further characterized the biological processes of the target genes by gene ontology annotation. Our results suggest that CEBPD-inducible genes with roles in the inhibition of apoptosis are downregulated and that BCL3-repressible genes are involved in the regulation of cellular metabolism in ICM. Moreover, our results suggest that CITED2 downregulation causes increased expression of HIF1A target genes. Functional analysis of HIF1A target genes revealed that hypoxic and stress response genes are activated in ICM. Finally, we found a significant correlation between the mRNA levels of BCL3 and the mRNA levels of both CEBPD (r = 0.73, p < 0.001) and CITED2 (r = 0.56, p < 0.05). Interestingly, CITED2 mRNA levels are directly related to ejection fraction (EF) (r = 0.54, p < 0.05). CONCLUSIONS: Our data indicate that changes in the expression of SP100, CITED2, CEBPD, and BCL3 affect their transcription regulatory networks, which subsequently alter a number of biological processes in ICM patients. The relationship between CITED2 mRNA levels and EF emphasizes the importance of this transcription factor in ICM. Moreover, our findings identify new mechanisms used to interpret gene expression changes in ICM and provide valuable resources for further investigation of the molecular basis of human cardiac ischemic response. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12920-015-0088-y) contains supplementary material, which is available to authorized users. BioMed Central 2015-03-29 /pmc/articles/PMC4386080/ /pubmed/25884818 http://dx.doi.org/10.1186/s12920-015-0088-y Text en © Herrer et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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 Article
Herrer, Isabel
Roselló-Lletí, Esther
Ortega, Ana
Tarazón, Estefanía
Molina-Navarro, María Micaela
Triviño, Juan Carlos
Martínez-Dolz, Luis
Almenar, Luis
Lago, Francisca
Sánchez-Lázaro, Ignacio
González-Juanatey, José Ramón
Salvador, Antonio
Portolés, Manuel
Rivera, Miguel
Gene expression network analysis reveals new transcriptional regulators as novel factors in human ischemic cardiomyopathy
title Gene expression network analysis reveals new transcriptional regulators as novel factors in human ischemic cardiomyopathy
title_full Gene expression network analysis reveals new transcriptional regulators as novel factors in human ischemic cardiomyopathy
title_fullStr Gene expression network analysis reveals new transcriptional regulators as novel factors in human ischemic cardiomyopathy
title_full_unstemmed Gene expression network analysis reveals new transcriptional regulators as novel factors in human ischemic cardiomyopathy
title_short Gene expression network analysis reveals new transcriptional regulators as novel factors in human ischemic cardiomyopathy
title_sort gene expression network analysis reveals new transcriptional regulators as novel factors in human ischemic cardiomyopathy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386080/
https://www.ncbi.nlm.nih.gov/pubmed/25884818
http://dx.doi.org/10.1186/s12920-015-0088-y
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