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Anthracyclines induce global changes in chromatin accessibility in cardiomyocytes that overlap with cardiovascular disease loci [CUT&Tag]

ABSTRACT: Breast cancer drugs can induce adverse effects on the heart in some women. Treatment with anthracyclines (ACs) or Trastuzumab increase the risk for cardiovascular diseases (CVD) such as atrial fibrillation (AF) and heart failure (HF) that ultimately affect the heart muscle. These CVD are associated with hundreds of genetic variants in non-coding regions of the genome. However, how these drugs affect the non-coding genome of the heart and CVD risk loci is unknown. We therefore measured chromatin accessibility across iPSC-derived cardiomyocytes from four individuals treated with the ACs, Doxorubicin, Epirubicin, and Daunorubicin, a related non-AC, Mitoxantrone, and the monoclonal antibody Trastuzumab, or a vehicle control for three and 24 hours. We identified 155,557 high-confidence regions of open chromatin across 48 samples where the major sources of variation are associated with treatment and time. Jointly modeling the data revealed three accessibility response signatures denoted as early acute, early-sustained, and late that correspond to 65,844 regions that open or close in response to drug treatment. Sequences associated with drug-induced chromatin opening contain motifs for DNA damage-associated transcription factors including p53 and ZBTB14, and associate with increases in active histone modifications and gene expression. 21 AF- and HF-associated SNPs directly overlap with regions associated with drug-induced opening. A shared intronic HF and AF SNP, rs3176326, that is also an eQTL for CDKN1A in heart tissue, associates with increased chromatin accessibility, histone acetylation and CDKN1A expression in response to all ACs. Our results demonstrate large-scale changes in chromatin accessibility in cardiomyocytes treated with ACs, which correspond to several regions harboring CVD risk loci.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291262 | GEO | 2025/06/17

REPOSITORIES: GEO

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Project description:Background: Atrial fibrillation (AF), a critical health and economic issue is common in patients with heart failure (HF). Meanwhile, HF is a leading complication of nonvalvular atrial fibrillation (NVAF), and the presence of both conditions is associated with worsen outcomes. Accumulating evidence has indicated that messenger RNA (mRNA), microRNA (miRNA) and circular RNA (circRNA) play vital roles in the occurrence and progression of HF and AF. However, the underlying molecular mechanism of HF with AF remains elusive. We aimed to investigate the role of circRNA/miRNA/mRNA regulatory network in HF with AF through High-throughput sequencing and bioinformatics analysis. Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from 4 patients who had heart failure with atrial fibrillation (HF /AF group) and 4 matched healthy subjects. RNA sequencing was performed to get circRNAs and mRNAs. miRNAs were obtained through miRanda and HMDD databases. qRT-PCR was used to verify our data. R software was employed for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The PPI network was completed using STRING. Immune infiltration analysis was performed using cibersort method. The ceRNA network of circRNA/miRNA/mRNA was constructed by Cytoscape. Results: Differential expression analysis showed that circRNAs (137 upregulated and 31 downregulated) and mRNAs (534 upregulated and 255 downregulated) were considered as significantly different between HF with AF group and control group. Immune infiltration analysis demonstrated that macrophages were obviously upregulated and mast cells were significantly downregulated in PBMCs of the HF/AF group. GO and KEGG analyses showed that HF with AF-related mRNAs were abundant in the pathway of programmed cell death (PCD) and myocardial remodeling. So we confirm that hsa_circ_0047870/hsa-miR-34a-5p/SMPD1, hsa_circ_0127340/hsa-miR-192-3p/FBXW5, hsa_circ_0002484/hsa-miR-26b-3p/PYCARD, hsa_circ_0047870/hsa-miR-20b-3p/HTRA2 and hsa_circ_0004027/hsa-miR-26a-5p/HIF1A ceRNA axes could promote the development of HF with AF through the PCD-related pathway. Conclusions: We suggested that the imbalance of immune cell composition in PBMCs may play an initial role in the progression of HF with AF. The PCD-related ceRNA regulatory network may be the potential therapeutic target in the occurrence and progression of HF with AF. The circRNAs could serve as novel diagnostic markers.

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Anthracyclines induce global changes in chromatin accessibility in cardiomyocytes that overlap with cardiovascular disease loci [CUT&Tag]

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