Linking chemicals, genes and morphological perturbations to diseases

Abstract

The progress in image-based high-content screening technology has facilitated high-throughput phenotypic profiling notably the quantification of cell morphology perturbation by chemicals. However, understanding the mechanism of action of a chemical and linking it to cell morphology and phenotypes remains a challenge in drug discovery. In this study, we intended to integrate molecules that induced transcriptomic perturbations and cellular morphological changes into a biological network in order to assess chemical-phenotypic relationships in humans. Such a network was enriched with existing disease information to suggest molecular and cellular profiles leading to phenotypes. Two datasets were used for this study. Firstly, we used the "Cell Painting morphological profiling assay" dataset, composed of 30,000 compounds tested on human osteosarcoma cells (named U2OS). Secondly, we used the "L1000 mRNA profiling assay" dataset, a collection of transcriptional expression data from cultured human cells treated with approximately 20,000 bioactive small molecules from the Library of Integrated Network-based Cellular Signatures (LINCS). Furthermore, pathways, gene ontology terms and disease enrichments were performed on the transcriptomics data. Overall, our study makes it possible to develop a biological network combining chemical-gene-pathway-morphological perturbation and disease relationships. It contains an ensemble of 9989 chemicals, 732 significant morphological features and 12,328 genes. Through diverse examples, we demonstrated that some drugs shared similar genes, pathways and morphological profiles that, taken together, could help in deciphering chemical-phenotype observations.

Keywords: Cell painting; Chemical-phenotypic relationship; Hepatotoxicity; Non-genotoxic carcinogen; Pharmacology; Transcriptomics.