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Identification of Upstream Transcriptional Regulators of Ischemic Cardiomyopathy Using Cardiac RNA-Seq Meta-Analysis.

ABSTRACT: Ischemic cardiomyopathy (ICM), characterized by pre-existing myocardial infarction or severe coronary artery disease, is the major cause of heart failure (HF). Identification of novel transcriptional regulators in ischemic HF can provide important biomarkers for developing new diagnostic and therapeutic strategies. In this study, we used four RNA-seq datasets from four different studies, including 41 ICM and 42 non-failing control (NF) samples of human left ventricle tissues, to perform the first RNA-seq meta-analysis in the field of clinical ICM, in order to identify important transcriptional regulators and their targeted genes involved in ICM. Our meta-analysis identified 911 differentially expressed genes (DEGs) with 582 downregulated and 329 upregulated. Interestingly, 54 new DEGs were detected only by meta-analysis but not in individual datasets. Upstream regulator analysis through Ingenuity Pathway Analysis (IPA) identified three key transcriptional regulators. TBX5 was identified as the only inhibited regulator (z-score = -2.89). F2R and SFRP4 were identified as the activated regulators (z-scores = 2.56 and 2.00, respectively). Multiple downstream genes regulated by TBX5, F2R, and SFRP4 were involved in ICM-related diseases such as HF and arrhythmia. Overall, our study is the first to perform an RNA-seq meta-analysis for clinical ICM and provides robust candidate genes, including three key transcriptional regulators, for future diagnostic and therapeutic applications in ischemic heart failure.

SUBMITTER: Alimadadi A

PROVIDER: S-EPMC7278960 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Identification of Upstream Transcriptional Regulators of Ischemic Cardiomyopathy Using Cardiac RNA-Seq Meta-Analysis.

Alimadadi Ahmad A Aryal Sachin S Manandhar Ishan I Joe Bina B Cheng Xi X

International journal of molecular sciences 20200514 10

Ischemic cardiomyopathy (ICM), characterized by pre-existing myocardial infarction or severe coronary artery disease, is the major cause of heart failure (HF). Identification of novel transcriptional regulators in ischemic HF can provide important biomarkers for developing new diagnostic and therapeutic strategies. In this study, we used four RNA-seq datasets from four different studies, including 41 ICM and 42 non-failing control (NF) samples of human left ventricle tissues, to perform the firs ...[more]

PMID: 32423033

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Project description:BackgroundIschemic 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.MethodsMyocardial tissue explants from ICM patients and control (CNT) subjects were analyzed by RNA-Sequencing (RNA-Seq) and quantitative Real-Time PCR.ResultsEnrichment 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).ConclusionsOur 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.

Dataset Information

Identification of Upstream Transcriptional Regulators of Ischemic Cardiomyopathy Using Cardiac RNA-Seq Meta-Analysis.

Publications

Identification of Upstream Transcriptional Regulators of Ischemic Cardiomyopathy Using Cardiac RNA-Seq Meta-Analysis.

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