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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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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. |
format | Online Article Text |
id | pubmed-4386080 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
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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