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Published on: February 3, 2023
Identification of Upstream Transcriptional Regulators of Ischemic Cardiomyopathy Using Cardiac RNA-Seq Meta-Analysis
Ahmad Alimadadi1,2, Sachin Aryal1,2, Ishan Manandhar1,2
1Center for Hypertension and Precision Medicine, Program in Physiological Genomics, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA.
Insights
This study identified key gene regulators in ischemic cardiomyopathy (ICM) using RNA-sequencing meta-analysis. These findings offer potential biomarkers for diagnosing and treating heart failure (HF).
Area of Science:
- Genomics
- Cardiovascular Research
- Molecular Biology
Background:
- Ischemic cardiomyopathy (ICM) is a primary cause of heart failure (HF), often stemming from myocardial infarction or coronary artery disease.
- Identifying novel transcriptional regulators in ICM is crucial for developing diagnostic biomarkers and therapeutic strategies.
- Existing research often relies on individual studies, potentially missing broader patterns in gene expression.
Purpose of the Study:
- To conduct the first RNA-sequencing (RNA-seq) meta-analysis on human left ventricle tissues from patients with clinical Ischemic Cardiomyopathy (ICM).
- To identify key transcriptional regulators and their downstream target genes involved in the pathophysiology of ICM.
- To discover novel candidate genes for diagnostic and therapeutic applications in ischemic heart failure.
Main Methods:
- Integrated four RNA-seq datasets comprising 41 ICM and 42 non-failing control (NF) human left ventricle samples.
- Performed a meta-analysis to identify differentially expressed genes (DEGs) between ICM and NF groups.
- Utilized Ingenuity Pathway Analysis (IPA) for upstream regulator analysis to identify key transcriptional regulators.
Main Results:
- Identified 911 differentially expressed genes (DEGs) in ICM, with 582 downregulated and 329 upregulated.
- Discovered 54 novel DEGs unique to the meta-analysis, not found in individual datasets.
- Identified three key transcriptional regulators: TBX5 (inhibited, z-score = -2.89), F2R (activated, z-score = 2.56), and SFRP4 (activated, z-score = 2.00).
- Downstream genes regulated by TBX5, F2R, and SFRP4 are implicated in heart failure and arrhythmia.
Conclusions:
- This RNA-seq meta-analysis provides a robust identification of DEGs and key transcriptional regulators in clinical ICM.
- TBX5, F2R, and SFRP4 emerge as significant regulators potentially driving ICM pathogenesis.
- The identified regulators and their target genes represent promising candidates for future diagnostic and therapeutic interventions in ischemic heart failure.
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.
