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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 including anthracyclines (ACs) and Trastuzumab increase the risk for cardiovascular diseases (CVDs) such as atrial fibrillation (AF) and heart failure (HF) that ultimately affect the heart muscle. These CVDs are associated with hundreds of genetic variants in non-coding regions of the genome. However, how these drugs affect the regulatory potential of the non-coding genome of the heart and CVD risk loci is unknown. We therefore measured global chromatin accessibility across iPSC-derived cardiomyocytes derived from four healthy individuals that we treated with topoisomerase II (TOP2) inhibiting ACs, Doxorubicin, Epirubicin, and Daunorubicin, and the anthracenedione, Mitoxantrone as well as the TOP2-independent monoclonal antibody Trastuzumab, for three and 24 hours. We identified tens of thousands of open chromatin regions that are differentially accessible in response to TOP2 inhibitor treatments over time, and no changes in response to Trastuzumab. Early AC-responsive regions are promoter-proximal and are enriched for regions bound by TOP2 beta. Late AC-responsive regions are enriched for AC response genes particularly those associated with mismatch repair. AC-response regions near AC response genes are enriched for FOS:JUNB transcription factor motifs. Three AC-induced cardiotoxicity-, 28 AF- and 14 HF-associated SNPs directly overlap late AC-responsive regions. Early AC-responsive regions are enriched for AF SNPs including rs3176326, which is also associated with HF, and is an eQTL for CDKN1A in heart tissue. This SNP associates with increased chromatin accessibility at a TOP2 beta-bound region, increased histone acetylation, and increased 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 AF and HF risk loci. The identified drug-responsive chromatin regions can be used to annotate variants in cancer patient populations to contribute to risk estimation for CVD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291262 | GEO | 2025/06/17

REPOSITORIES: GEO

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Project description:Breast cancer drugs including anthracyclines (ACs) and Trastuzumab increase the risk for cardiovascular diseases (CVDs) such as atrial fibrillation (AF) and heart failure (HF) that ultimately affect the heart muscle. These CVDs are associated with hundreds of genetic variants in non-coding regions of the genome. However, how these drugs affect the regulatory potential of the non-coding genome of the heart and CVD risk loci is unknown. We therefore measured global chromatin accessibility across iPSC-derived cardiomyocytes derived from four healthy individuals that we treated with topoisomerase II (TOP2) inhibiting ACs, Doxorubicin, Epirubicin, and Daunorubicin, and the anthracenedione, Mitoxantrone as well as the TOP2-independent monoclonal antibody Trastuzumab, for three and 24 hours. We identified tens of thousands of open chromatin regions that are differentially accessible in response to TOP2 inhibitor treatments over time, and no changes in response to Trastuzumab. Early AC-responsive regions are promoter-proximal and are enriched for regions bound by TOP2 beta. Late AC-responsive regions are enriched for AC response genes particularly those associated with mismatch repair. AC-response regions near AC response genes are enriched for FOS:JUNB transcription factor motifs. Three AC-induced cardiotoxicity-, 28 AF- and 14 HF-associated SNPs directly overlap late AC-responsive regions. Early AC-responsive regions are enriched for AF SNPs including rs3176326, which is also associated with HF, and is an eQTL for CDKN1A in heart tissue. This SNP associates with increased chromatin accessibility at a TOP2 beta-bound region, increased histone acetylation, and increased 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 AF and HF risk loci. The identified drug-responsive chromatin regions can be used to annotate variants in cancer patient populations to contribute to risk estimation for CVD.

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.

Project description:Background: Acute coronary syndromes (ACS) are associated with aberrant gene expression and epigenetic mechanisms. In particular, de novo DNA methylation is typically linked to gene silencing, but its role in heart disease remains not fully understood. Extracellular vesicles (EVs) are active components in cellular communication for their ability to carry a plethora of signalling biomolecules, thus representing a promising new diagnostic/therapeutic approach in cardiovascular diseases (CVDs). Indeed, there is the need of novel biomarkers for ACS prediction and timely detection. Purpose: We hypothesized that specific epigenetic signals can be carried by EVs. In this regard, we isolated and characterized circulating EVs from ACS patients and evaluated their potential role to influence DNA methylation in target cells. Methods: Circulating EVs were recovered, by ultracentrifugation, from plasma samples of 19 ACS patients and 50 healthy subjects (HS). Nanoparticle tracking analysis (NTA) and western blot (WB) were used to confirm the EVs integrity and purity. Peripheral blood mononuclear cells (PBMCs) of volunteer donors were treated with both ACS and HS derived EVs and genomic DNA was extracted to perform epigenome wide analysis through Reduced Representation Bisulfite Sequencing. ShinyGO, PANTHER, and STRING tools were interrogated to perform GO and PPI network analyses. Flow Cytometry, qRT-PCR, and WB analysis were also performed to evaluate and validate both intra-vesicular and intra-cellular signals. Results: Plasma ACS-derived EVs showed a significant up-regulation of DNA methyltransferases (DNMTs) gene expression levels as compared to HS (P<0.001). Specifically, de novo methylation transcripts, as DNMT3A and DNMT3B were significantly increased in plasma ACS-EVs. DNA methylation analysis of PBMCs from volunteer donors treated with HS- and ACS-derived EVs showed that RNF166 and CCND3 genes resulted the most hyper- and hypo-methylated, respectively, after by ACS-EV treatment. In addition, PPI network analysis specifically evidenced the subnetwork with SRC, as a hub gene, connecting it to NOTCH1, FOXO3, CDC42, IKBKG, RXRA, DGKG, known as important genes already involved in the onset of CVDs. Surprising, other novel genes, BAIAP2, SYP, CHL1, and SHB, which were hypomethylated, were found significantly overexpressed in PBMCs (P<0.005), underlying the fundamental modulating properties of EV cargo in atherosclerosis. Conclusions: These findings support the significant role of ACS plasma-derived EVs, inducing de novo DNA methylation signals, and modulating specific signaling pathways in target cells.

Project description:TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. There is no drug- or AC-specific signature. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified 38 genes in loci associated with AC toxicity by GWAS or TWAS. Two thirds of the genes that respond to at least one TOP2i, respond to all ACs with the same direction of effect. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.

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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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