Biology subjects

McIntire, E.

Publications and source records attributed to McIntire, E..

4 recordsLinked to original sources

bioRxiv2026

Genetic Determinants of Cell-Type-Specific Responses to Cardiotoxic Chemotherapeutic Agents

Doxorubicin (DOX) and 5-fluorouracil (5-FU) are effective for treating a variety of cancers, yet many patients taking these drugs experience adverse cardiovascular events that are severe enough to pause treatment, often prolonging the course of chemotherapy and reducing its efficacy. Individual risk for drug-induced cardiotoxicity is likely mediated, at least in part, by genetic variants that control how the heart and vasculature respond to drug-induced perturbations. To identify loci associated with drug-induced cardiotoxicity, we developed an in vitro model that allows us to characterize the effects of chemotherapeutic drugs on a wide range of cardiac cell types, including cardiomyocytes, endothelial cells, and fibroblasts. Using single-cell RNA-seq, we profiled responses to DOX and 5-FU across 46 individuals and 14 cell types, identifying hundreds of expression quantitative trait loci that modify cardiovascular transcription in response to each drug (response eQTLs). Drug-responsive eQTL genes include genes that were previously linked to drug-induced cardiotoxicity and cardiovascular disease, such as ABCB4, HAS3, TNFRSF1A, and OGFR. Over a third of drug-responsive genes are shared between the DOX and 5-FU treatments, suggesting that genes predictive of DOX-induced cardiotoxicity may extend to 5-FU. Among the credible colocalizations we identified between GWAS signals and drug-response eQTLs, we discovered a locus associated with ischemic heart disease that is also a DOX-responsive eQTL for IL6R. IL6R was previously nominated as a druggable target for heart disease, and its binding partner IL6 is a candidate biomarker for anthracycline-induced cardiotoxicity. These findings advance the discovery of genetic variants underlying cardiotoxicity and support development of genotype-based predictors for treating cancer.

genomics↗

bioRxiv2026

Beyond the mean: genetic control of gene expression fidelity and dispersion

For decades, molecular biologists have interpreted gene regulation through measurements of mean gene expression, because they could not resolve regulatory variation among individual cells. The advent of single-cell genomics has now made that variation measurable, revealing pervasive differences in gene expression among apparently similar cells. Whether this variation mainly reflects stochastic noise or an informative regulatory property remains unclear. Here we show that mean-corrected gene expression dispersion is a reproducible and biologically structured feature of gene regulation that reflects regulatory fidelity. In heterogeneous differentiated cardiac cultures, genes with low dispersion are shared across cell types, enriched for housekeeping functions, depleted for expression quantitative trait loci, and more highly connected in transcriptional and protein interaction networks. In a comparative single-cell system spanning human, chimpanzee, and allotetraploid cells, a substantial subset of interspecies differences in regulatory dispersion persists in a shared trans environment, indicating that gene expression fidelity is often regulated in cis. Our findings establish gene expression dispersion as a genetically encoded dimension of gene regulation that is distinct from mean expression, and places dispersion along a fidelity-plasticity axis with implications for development, disease, and threshold-dependent cellular phenotypes.

genomics↗

bioRxiv2024

Chromosome X Dosage Modulates Development of Aneuploidy in Genetically Diverse Mouse Embryonic Stem Cells

The genetic integrity of pluripotent stem cells (PSC) is critical to their applications in research and therapy, but it is compromised by frequent development of structural chromosome variants associated with malignancy. Many cell lines exhibit remarkable genetic stability, but little is known about the basis of the known variation in genomic integrity amongst different PSC isolates. Here we identify aneuploidies using RNA-seq and proteomics data from a panel of mouse embryonic stem cell (mESC) lines derived from 170 Diversity Outbred mice. We found 62 lines with detectable aneuploid subpopulations and a subset of originally XX lines that lost one Chromosome X (XO). Strikingly, a much lower proportion of XX lines were aneuploid, compared to XY or XO lines. Two single-cell RNA-seq data sets demonstrated that aneuploid XY DO mESC also show lower Chromosome X gene expression, and a prospective study confirmed that XY mESC accumulate higher aneuploid proportions in culture than isogenic XX lines. We identify potential mechanisms for this protective effect of X chromosome dosage, including our findings that the lines with two active X Chromosomes have a higher proportion of 2-cell-like cells, a state associated with maintenance of genetic integrity of mESC, and that they show differential expression of X-linked tumor suppressor genes associated with the DNA damage response. HighlightsO_LIFirst genetic analysis of predisposition to aneuploidy in pluripotent stem cell cultures C_LIO_LIChromosomal regions duplicated in aneuploid mouse embryonic stem cells are syntenic with regions overrepresented in human pluripotent stem cell lines bearing recurrent genetic abnormalities C_LIO_LIX-Chromosome dosage strongly influences susceptibility to aneuploidy in mouse embryonic stem cells and to a lesser degree in human pluripotent stem cells C_LIO_LIXX mouse embryonic stem cell lines show a higher proportion of cells in 2 cell-like state and higher expression of tumor suppressor genes associated with DNA damage response C_LI

genetics↗

bioRxiv2023

Guided Differentiation of Pluripotent Stem Cells for Cardiac Cell Diversity

In principle, induced pluripotent stem cells (iPSCs) can differentiate into any cell type in the body. The challenge is to find a way to rapidly expand the dimensionality of cell types and cell states we can characterize. To address this, we developed a guided differentiation protocol to produce heterogeneous differentiating cultures of cardiac cell types (cardiac HDCs) in 16 days. Cardiac HDCs are three-dimensional, rhythmically contracting cell aggregates that harbor a temporally and functionally diverse range of cardiac-relevant cell types. We characterize cardiac HDCs from 47 iPSC lines using single-cell RNA-sequencing to identify cardiomyocytes, epicardial cells, cardiac fibroblasts, endothelial cells, and hematopoietic cells, along with both ectodermal and endodermal derivatives. This guided differentiation approach prioritizes simplicity by minimizing the reagents and steps required, thereby enabling rapid and cost-effective experimental throughput. We expect cardiac HDCs to provide a scalable cardiac model for population-level studies of gene regulatory variation and gene-by-environment interactions.

genomics↗