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

• Main Authors: Ahmad Alimadadi, Sachin Aryal, Ishan Manandhar, Bina Joe, Xi Cheng
• Format: Article
• Language: English
• Published: MDPI AG 2020-05-01
• Series: International Journal of Molecular Sciences
• Subjects: ischemic cardiomyopathy; heart failure; transcriptional regulators; meta-analysis; RNA-seq
• Online Access: https://www.mdpi.com/1422-0067/21/10/3472
• ISSN: 1661-6596; 1422-0067

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. <i>TBX5</i> was identified as the only inhibited regulator (<i>z</i>-score = −2.89). <i>F2R</i> and <i>SFRP4</i> were identified as the activated regulators (<i>z</i>-scores = 2.56 and 2.00, respectively). Multiple downstream genes regulated by <i>TBX5</i>, <i>F2R</i>, and <i>SFRP4</i> 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.