Biology subjects

Matthews, E. R.

Publications and source records attributed to Matthews, E. R..

3 recordsLinked to original sources

bioRxiv2026

Conserved RNA-protein modules link early anthracycline responses to atrial fibrillation risk

Anthracycline chemotherapeutics increase risk for cardiovascular disease. The early molecular events that link inherited risk to cardiac dysfunction remain poorly defined. We therefore exposed iPSC-derived cardiomyocytes from six individuals to three anthracyclines and an anthracenedione, which act as topoisomerase inhibitors (TOP2i) to induce DNA damage, and generated proteomics data following three and 24 hours of TOP2i treatment. We constructed a 19 module co-expression network and identified four protein modules that associate with response to all TOP2i. Integration with a co-expression network generated from paired transcriptomic data revealed that the two most drug-responsive protein modules are preserved in the RNA network. The most preserved RNA module is enriched for p53 motifs in associated active regulatory regions and p53 target genes, which propagates to enrichment of p53 targets in the most drug-responsive preserved protein module. Integration of the protein network with genome-wide association studies across hundreds of cardiovascular traits identified a preserved protein module enriched for genetic risk of atrial fibrillation, PR interval, and longitudinal strain, suggesting that the molecular response to TOP2i is linked to genetic variation influencing cardiac electrophysiology and contractile performance. Differential protein abundance in this module associates with impaired calcium handling in cardiomyocytes thereby linking molecular effects to cellular decline. Together, these results define a TOP2i-induced gene regulatory response propagated to the proteome that underlies early cardiotoxicity, and demonstrate how a multi-level network architecture can provide insight into genetically mediated susceptibility to drug-induced stress.

genomics↗

bioRxiv2025

Anthracyclines induce global changes in cardiomyocyte chromatin accessibility that overlap with cardiovascular disease loci

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 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 drug type and time. Jointly modeling the data revealed three accessibility response signatures denoted as early-acute, early-sustained, and late that correspond to 67,329 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 acetylation 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. Author summaryAnthracyclines are a widely used class of breast cancer drugs that are linked to cardiac toxicity and the development of heart disease in some women. There are hundreds of genetic variants that associate with risk for heart disease; however their role and mechanism of action in drug- induced toxicity is unclear given that most reside in the non-coding genome. We therefore tested the effects of five breast cancer drugs on genome-wide chromatin accessibility using induced pluripotent stem cell-derived cardiomyocytes. We found tens of thousands of chromatin regions that change in accessibility after drug treatment. Regions with increased accessibility contain sequences that have been shown to bind DNA damage-associated transcription factors, and associate with increases in nearby gene expression. We find 21 heart disease-associated genetic variants in regions that increase in chromatin accessibility following treatment. This suggests that cancer drugs have large effects on the non-coding genome of heart cells including at regions associated with heart disease. This research contributes to our understanding of how genetic variants associated with disease exert their effects.

genomics↗

bioRxiv2023

Anthracycline-induced cardiotoxicity associates with a shared gene expression response signature to TOP2-inhibiting breast cancer drugs in cardiomyocytes

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. 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 eight genes in loci associated with AC toxicity by GWAS or TWAS. All eight genes, including RARG and SLC28A3, respond to at least two ACs, and their expression correlates with the release of cardiotoxicity markers. 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. Author summaryAnthracycline drugs such as Doxorubicin are effective treatments for breast cancer; however, they can cause cardiotoxicity in some women. It is unclear whether women would experience the same toxicity for all drugs in this class, or whether specific drugs would be better tolerated in specific individuals. We used an in vitro system of induced pluripotent stem cell-derived cardiomyocytes from six healthy females to test the effects of five breast cancer drugs on cell heath and global gene expression. We identified a strong shared cellular and gene expression response to drugs from the same class. However, there is more variation in gene expression levels between individuals following treatment with each anthracycline compared to untreated cells. We found that genes in regions previously associated with Doxorubicin-induced cardiotoxicity in cancer patients, respond to at least two drugs in the class. This suggests that drugs in the same class induce similar effects on an individuals heart. This work contributes to our understanding of how drug response, in the context of off-target effects, varies across individuals.

genomics↗