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.
Highlights
Heart failure (HF), leading to considerable mortality and health care costs, is a critical health problem, especially among the people aged ≥65, around the world [1]
We used four RNA-seq datasets from four different RNA-seq studies, including 41 ischemic cardiomyopathy (ICM) and 42 non-failing control (NF) samples of human left ventricle tissues, to perform the first RNA-seq meta-analysis for identifying key transcriptional regulators involved in clinical ICM
Integrating the results of the TBX5-targeted genes and the differentially expressed genes (DEGs) in toxicity pathways, we found that the dysregulation of TBX5-targeted genes, TNNT2, NPPA, TTN, ATP2A2, DES and SCN5A, contributed to the development of heart failure and arrhythmia (Figures 2C and 4A)
Summary
Heart failure (HF), leading to considerable mortality and health care costs, is a critical health problem, especially among the people aged ≥65, around the world [1]. Mild or severe repeated injuries to left ventricle are common in patients with ICM, resulting in cardiac remodeling, chronic myocardial dysfunction and eventual HF [3]. Dysregulated transcriptional hubs, such as transcription factors, non-coding RNAs and chromatin regulators, and their downstream gene expression signatures are representative of genomic mechanisms underlying disease processes. Detecting such genomic signatures aids in the development of new diagnostic and therapeutic approaches. We used four RNA-seq datasets from four different RNA-seq studies, including 41 ICM and 42 non-failing control (NF) samples of human left ventricle tissues, to perform the first RNA-seq meta-analysis for identifying key transcriptional regulators involved in clinical ICM
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