整合DNA甲基化组和转录组分析确定了与扩张型心肌病相关心力衰竭影响的潜在基因。

Integrative DNA methylome and transcriptome analysis identify potential genes on the influence of dilated cardiomyopathy-associated heart failure.

作者信息

Guo Zhenglong, Liu Yunfei, Zhou Zhiming, Chen Jianchao, Guo Lin, Liang Keke, Hao Yibin, Hao Bingtao, Yang Bin, Liao Shixiu

机构信息

Henan 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.

School of Medicine, People's Hospital of Henan University, Henan University, Zhengzhou, China.

出版信息

Clin Epigenetics. 2025 Apr 28;17(1):64. doi: 10.1186/s13148-025-01876-2.

DOI:10.1186/s13148-025-01876-2

PMID:40296161

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12036135/

Abstract

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.

摘要

目的

扩张型心肌病（DCM）相关的心力衰竭（HF）带来了重大的临床挑战，其潜在的表观遗传机制仍知之甚少。本研究旨在探讨DCM相关HF（DCM-HF）患者心脏中DNA甲基化与基因表达之间的相互作用。

方法

从五名健康供体和五名因DCM导致心力衰竭的心脏移植受者中采集心房组织。我们进行了RNA测序（RNA-seq）以分析mRNA表达谱，并进行了全基因组亚硫酸氢盐测序（WGBS）以评估DNA甲基化水平。通过将差异表达基因（DEG）与位于启动子区域的差异甲基化区域（DMR）相关基因整合，对RNA-seq和WGBS数据进行相关性分析。

结果

RNA-seq分析共鉴定出681个DEG，其中DCM-HF组织中有406个基因显著下调，275个基因上调，这些基因在与心肌病相关的通路中富集。WGBS揭示了16,158个低甲基化和6,857个高甲基化的差异甲基化区域（DMR），其中3,185个位于启动子区域。将启动子低甲基化和高甲基化DMR相关基因（DMG）与DEG整合，鉴定出46个与心脏发育和功能相关的枢纽基因。蛋白质-蛋白质相互作用和疾病关联分析突出了五个关键基因——NPPA、NPPB、ACTN2、NEBL和MYO18B——这些基因表现出启动子低甲基化和表达增加，可能与HIF1A和KLF4等转录因子的活性有关。