Multiscale mapping of transcriptomic signatures for cardiotoxic drugs Journal Article
| Authors: | Hansen, J.; Xiong, Y.; Siddiq, M. M.; Dhanan, P.; Hu, B.; Shewale, B.; Yadaw, A. S.; Jayaraman, G.; Tolentino, R. E.; Chen, Y.; Martinez, P.; Beaumont, K. G.; Sebra, R.; Vidovic, D.; Schürer, S. C.; Goldfarb, J.; Gallo, J. M.; Birtwistle, M. R.; Sobie, E. A.; Azeloglu, E. U.; Berger, S. I.; Chan, A.; Schaniel, C.; Dubois, N. C.; Iyengar, R. |
| Article Title: | Multiscale mapping of transcriptomic signatures for cardiotoxic drugs |
| Abstract: | Drug-induced gene expression profiles can identify potential mechanisms of toxicity. We focus on obtaining signatures for cardiotoxicity of FDA-approved tyrosine kinase inhibitors (TKIs) in human induced-pluripotent-stem-cell-derived cardiomyocytes, using bulk transcriptomic profiles. We use singular value decomposition to identify drug-selective patterns across cell lines obtained from multiple healthy human subjects. Cellular pathways affected by cardiotoxic TKIs include energy metabolism, contractile, and extracellular matrix dynamics. Projecting these pathways to published single cell expression profiles indicates that TKI responses can be evoked in both cardiomyocytes and fibroblasts. Integration of transcriptomic outlier analysis with whole genomic sequencing of our six cell lines enables us to correctly reidentify a genomic variant causally linked to anthracycline-induced cardiotoxicity and predict genomic variants potentially associated with TKI-induced cardiotoxicity. We conclude that mRNA expression profiles when integrated with publicly available genomic, pathway, and single cell transcriptomic datasets, provide multiscale signatures for cardiotoxicity that could be used for drug development and patient stratification. © The Author(s) 2024. |
| Keywords: | controlled study; treatment response; human cell; genetics; bevacizumab; doxorubicin; sunitinib; metabolism; homologous recombination; gene expression; gene expression profiling; protein kinase inhibitor; cell line; cell renewal; food and drug administration; drug effect; drug development; transcriptomics; protein tyrosine kinase inhibitor; protein kinase inhibitors; endothelium cell; extracellular matrix; gene mapping; messenger rna; cardiotoxicity; daunorubicin; pazopanib; vandetanib; fibroblast; fibroblasts; genomics; epirubicin; down regulation; upregulation; idarubicin; toxicity; trastuzumab; anthracycline; energy metabolism; transcriptome; lapatinib; quantitative trait locus; chromatin assembly and disassembly; induced pluripotent stem cells; canonical wnt signaling; etiology; citric acid cycle; single cell analysis; single-cell analysis; data set; myocytes, cardiac; nucleotide excision repair; procedures; sarcomere; muscle contraction; dabrafenib; induced pluripotent stem cell; heart muscle contractility; ponatinib; humans; human; article; whole genome sequencing; mitochondrial dynamics; differential gene expression; cells by body anatomy; heart fibroblast; smooth muscle cell; mrna expression level; cardiac muscle cell; single cell rna seq; pathway enrichment analysis; mavacamten; outlier; singular value decomposition; epicardium |
| Journal Title: | Nature Communications |
| Volume: | 15 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-09-11 |
| Start Page: | 7968 |
| Language: | English |
| DOI: | 10.1038/s41467-024-52145-4 |
| PUBMED: | 39261481 |
| PROVIDER: | scopus |
| PMCID: | PMC11390749 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
