Multiscale mapping of transcriptomic signatures for cardiotoxic drugs.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 Sep 2024
11 Sep 2024
Historique:
received:
24
02
2023
accepted:
27
08
2024
medline:
12
9
2024
pubmed:
12
9
2024
entrez:
11
9
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39261481
doi: 10.1038/s41467-024-52145-4
pii: 10.1038/s41467-024-52145-4
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7968Subventions
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : 5U54HG008098
Organisme : U.S. Department of Health & Human Services | U.S. Food and Drug Administration (U.S. Food & Drug Administration)
ID : 75F40119C10021
Informations de copyright
© 2024. The Author(s).
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