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Integrative DNA methylome and transcriptome analysis identify potential genes on the influence of dilated
Zhenglong Guo1,2, Yunfei Liu3,4, Zhiming Zhou3
1Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics and Medical, Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China.
Insights
Epigenetic changes in DNA methylation and gene expression are linked to dilated cardiomyopathy-associated heart failure (DCM-HF). Identifying key genes and pathways offers potential for new diagnostic and therapeutic strategies for DCM-HF.
Area of Science:
- Cardiovascular epigenetics
- Molecular mechanisms of heart failure
- Gene expression regulation in cardiomyopathy
Background:
- Dilated cardiomyopathy-associated heart failure (DCM-HF) poses a significant clinical challenge.
- The underlying epigenetic mechanisms in DCM-HF remain poorly understood.
- Investigating DNA methylation and gene expression interplay is crucial for understanding DCM-HF pathogenesis.
Purpose of the Study:
- To investigate the interplay between DNA methylation and gene expression in DCM-HF.
- To identify key genes and pathways involved in the epigenetic dysregulation of DCM-HF.
- To explore potential diagnostic and therapeutic targets for DCM-HF.
Main Methods:
- Atrial tissues from DCM-HF patients and healthy donors were analyzed.
- RNA-sequencing (RNA-seq) was used to profile mRNA expression.
- Whole-genome bisulfite sequencing (WGBS) assessed DNA methylation levels.
- Integration of RNA-seq and WGBS data identified differentially expressed genes (DEGs) and differentially methylated regions (DMRs).
Main Results:
- 681 DEGs were identified, enriched in cardiomyopathy-related pathways.
- 16,158 hypomethylated and 6,857 hypermethylated DMRs were detected, with 3,185 in promoter regions.
- 46 hub genes were identified, including NPPA, NPPB, ACTN2, NEBL, and MYO18B, showing promoter hypomethylation and increased expression.
Conclusions:
- Epigenetic dysregulation of cardiac stress-response and structural genes contributes to DCM-HF pathogenesis.
- Promoter methylation levels in key loci may serve as diagnostic markers.
- These findings suggest novel therapeutic strategies for DCM-HF management.
Objective:
Dilated cardiomyopathy (DCM)-associated heart failure (HF) presents a significant clinical challenge, underlying epigenetic mechanisms remaining poorly understood. This study aims to investigate the interplay between DNA methylation and gene expression in the hearts of patients with DCM-associated HF (DCM-HF).
Methods:
Atrial tissues were collected from five healthy donors and five heart transplant recipients suffering from heart failure due to DCM. We conducted RNA-sequencing (RNA-seq) to analyze mRNA expression profiles and performed whole-genome bisulfite sequencing (WGBS) to evaluate DNA methylation levels. Correlation analyses between RNA-seq and WGBS data were executed by integrating differentially expressed genes (DEGs) with genes associated with differentially methylated regions (DMRs) located in the promoter regions.
Results:
The RNA-seq analysis identified a total of 681 DEGs, comprising 406 significantly downregulated genes and 275 upregulated genes in DCM-HF tissues, which were enriched in pathways related to cardiomyopathy. WGBS revealed 16,158 hypomethylated and 6,857 hypermethylated differentially methylated regions (DMRs), with 3,185 of these located in promoter regions. The integration of promoter-hypomethylated and hypermethylated DMRs-related genes (DMGs) with DEGs resulted in the identification of 46 hub genes associated with cardiac development and function. Protein-protein interaction and disease association analyses highlighted five key genes-NPPA, NPPB, ACTN2, NEBL, and MYO18B-that exhibited promoter hypomethylation and increased expression, potentially linked to the activity of transcription factors such as HIF1A and KLF4.
Conclusions:
These findings suggest that the epigenetic dysregulation of cardiac stress-response and structural genes contributes to the pathogenesis of DCM-HF. Furthermore, the detection of promoter methylation levels in these loci may offer new opportunities for developing diagnostic tools and therapeutic strategies for DCM-HF management.
