Integrated Methylome and Transcriptome Analysis in Chronic Chagas Cardiomyopathy Uncovers Alterations in Heart Development.

Abstract

Chagas disease, caused by Trypanosoma cruzi, remains a health concern worldwide. Its most severe clinical outcome, chronic Chagas cardiomyopathy (CCC), is marked by progressive cardiac dysfunction. Biological mechanisms underlying the differential development of CCC remain unclear. We hypothesized that alterations in the host DNA methylation and its influence on gene expression may contribute to this differential disease progression. We analyzed whole-blood methylation data from 42 CCC patients and 23 individuals with the indeterminate form, followed by an integrated transcriptomic analysis in a 22 individuals subset. We performed transcription factor (TF) and functional enrichment analyses to identify biological mechanisms underlying CCC severity. Severe CCC patients exhibited higher methylation variability, particularly in immune regulation genes. Integrated analysis revealed dysregulation of genes regulating cardiac development, morphogenesis, and ion homeostasis, with GATA5 as a key TF regulating cardiac pathways. TF activity inferred from peripheral blood resembled cardiac signatures previously described, with RUNX TFs, key drivers of Th1 immune polarization, correlating strongly with disease severity. Our findings highlight a systemic epigenetic signature in blood that reflects cardiac pathology in CCC. These insights advance our understanding of CCC pathogenesis and facilitate novel blood-based biomarkers and therapeutic targets aimed at preventing disease progression.