DNA Methylation Patterns of 5mC Regulators: Insights into Immune Microenvironment Regulation in Heart Failure.

Abstract

The 5-methylcytosine (5mC) epigenetic modification is a prominent pattern of DNA methylation. Nonetheless, its function and relationship with the immune microenvironment (IME) in heart failure (HF) are unclarified. Firstly, seven microarrays and two high-throughput sequencing datasets were downloaded from GEO for this research. Secondly, random forests, LASSO logistic regression, and SVM-RFE were leveraged for screening hub genes. Quantitative PCR, Western blot, and immunofluorescence staining were conducted in a male rat model of HF after myocardial infarction for validation. Thirdly, 5mC-related HF samples were allocated into two distinct categories using consensus clustering algorithms. Finally, single-sample gene-set enrichment analysis and CIBERSORT deconvolution algorithm were utilized for further exploring the IME in HF, including infiltrating immune cell abundance score, human leukocyte antigen (HLA), and immune checkpoints (ICPs). Among these 5mC regulators, four hub genes were uncovered, and the diagnostic model exhibited an outstanding ability to distinguish HF and healthy samples (0.969, 95%CI, 0.953-0.985). DNMT3B was identified as greatly influencing cardiac function. DNMT3B and MBD2 were finally identified as hub genes in the HF model. Two 5mC subtypes manifested different modification patterns, infiltrating immunocytes, ICPs, and HLA gene expression. Furthermore, 305 DEGs were found in 5mC subtypes, and many functions were associated with important pathophysiological mechanisms of HF. The HF diagnostic model was established using 5mC robust core biomarkers. 5mC methylation regulators may offer novel perspectives for understanding the mechanisms, accurate diagnosis, and effective interventions for HF.