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Integrated Methylome and Transcriptome Analysis in Chronic Chagas Cardiomyopathy Uncovers Alterations in Heart
Francisco Heredia-Fernández1, Javier Martínez-López1,2, Laura C Terrón-Camero1
1Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain.
Insights
Altered DNA methylation in blood may predict chronic Chagas cardiomyopathy (CCC) severity. This epigenetic signature, particularly in immune genes, reflects cardiac damage and offers potential biomarkers for Chagas disease progression.
Area of Science:
- Epigenetics and Genomics
- Infectious Diseases
- Cardiovascular Research
Background:
- Chagas disease, caused by Trypanosoma cruzi, is a global health concern.
- Chronic Chagas cardiomyopathy (CCC) leads to progressive cardiac dysfunction.
- Mechanisms driving differential CCC development are not fully understood.
Purpose of the Study:
- To investigate the role of host DNA methylation and gene expression in CCC pathogenesis.
- To identify epigenetic alterations associated with differential CCC progression.
Main Methods:
- Whole-blood DNA methylation analysis in 42 CCC patients and 23 indeterminate cases.
- Integrated transcriptomic analysis in a subset of 22 individuals.
- Transcription factor (TF) and functional enrichment analyses were performed.
Main Results:
- Severe CCC patients showed increased methylation variability, especially in immune regulation genes.
- Dysregulated genes involved in cardiac development, morphogenesis, and ion homeostasis were identified.
- GATA5 emerged as a key TF in cardiac pathways; RUNX TFs correlated with disease severity.
Conclusions:
- A systemic epigenetic signature in blood correlates with cardiac pathology in CCC.
- Findings suggest blood-based epigenetic markers for CCC.
- Potential for novel therapeutic targets to prevent Chagas disease progression.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
