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Changes in transcriptomic landscape in human end-stage heart failure with distinct etiology.

ABSTRACT: Heart failure (HF) is the ultimate outcome of a variety of heart diseases, including restrictive cardiomyopathy (RCM), ischemic heart disease (IHD), and valvular heart disease (VHD). To date, accumulating evidence has suggested an important role of noncoding RNAs (ncRNAs) in HF. We performed RNA-sequencing studies with myocardial mRNAs/lncRNAs/circRNAs/miRNAs from non-failing hearts (donor heart tissue from heart transplantation) and three groups of patients with HF (RCM, IHD, and VHD). HF-related gene regulatory networks and gene co-expression networks were constructed based on the interaction relationship and expression profiles of differentially expressed mRNAs/ncRNAs. Our results indicated that HF with different etiologies is regulated by complex lncRNA/circRNA/miRNA/mRNA regulatory networks, comprising common pathways that are shared by all HF types as well as distinct pathways that are enriched in specific HF types. In addition, the HF biomarkers identified in our study have an important clinical application value in HF staging and HF type diagnosis.

SUBMITTER: Zhu M

PROVIDER: S-EPMC8894266 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Changes in transcriptomic landscape in human end-stage heart failure with distinct etiology.

Zhu Miaomiao M Zhang Chao C Zhang Zhe Z Liao Xudong X Ren Dongfeng D Li Rui R Liu Shiliang S He Ximiao X Dong Nianguo N

iScience 20220217 3

Heart failure (HF) is the ultimate outcome of a variety of heart diseases, including restrictive cardiomyopathy (RCM), ischemic heart disease (IHD), and valvular heart disease (VHD). To date, accumulating evidence has suggested an important role of noncoding RNAs (ncRNAs) in HF. We performed RNA-sequencing studies with myocardial mRNAs/lncRNAs/circRNAs/miRNAs from non-failing hearts (donor heart tissue from heart transplantation) and three groups of patients with HF (RCM, IHD, and VHD). HF-relat ...[more]

PMID: 35252820

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Project description:Heart failure (HF) is a leading cause of morbidity and mortality in the United States and worldwide. As a multifactorial syndrome with unpredictable clinical outcomes, identifying the common molecular underpinnings that drive HF pathogenesis remains a major focus of investigation. Disruption of cardiac gene expression has been shown to mediate a common final cascade of pathological hallmarks wherein the heart reactivates numerous developmental pathways. Although the central regulatory mechanisms that drive this cardiac transcriptional reprogramming remain unknown, epigenetic contributions are likely. In the current study, we examined whether the epigenome, specifically DNA methylation, is reprogrammed in HF to potentiate a pathological shift in cardiac gene expression. To accomplish this, we used paired-end whole genome bisulfite sequencing and next-generation RNA sequencing of left ventricle tissue obtained from seven patients with end-stage HF and three nonfailing donor hearts. We found that differential methylation was localized to promoter-associated cytosine-phosphate-guanine islands, which are established regulatory regions of downstream genes. Hypermethylated promoters were associated with genes involved in oxidative metabolism, whereas promoter hypomethylation enriched glycolytic pathways. Overexpression of plasmid-derived DNA methyltransferase 3A in vitro was sufficient to lower the expression of numerous oxidative metabolic genes in H9c2 rat cardiomyoblasts, further supporting the importance of epigenetic factors in the regulation of cardiac metabolism. Last, we identified binding-site competition via hypermethylation of the nuclear respiratory factor 1 (NRF1) motif, an established upstream regulator of mitochondrial biogenesis. These preliminary observations are the first to uncover an etiology-independent shift in cardiac DNA methylation that corresponds with altered metabolic gene expression in HF.NEW & NOTEWORTHY The failing heart undergoes profound metabolic changes because of alterations in cardiac gene expression, reactivating glycolytic genes and suppressing oxidative metabolic genes. In the current study, we discover that alterations to cardiac DNA methylation encode this fetal-like metabolic gene reprogramming. We also identify novel epigenetic interference of nuclear respiratory factor 1 via hypermethylation of its downstream promoter targets, further supporting a novel contribution of DNA methylation in the metabolic remodeling of heart failure.

Dataset Information

Changes in transcriptomic landscape in human end-stage heart failure with distinct etiology.

Publications

Changes in transcriptomic landscape in human end-stage heart failure with distinct etiology.

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