Estimating Intraclonal Heterogeneity and Subpopulation Changes from Perturbational Bulk Gene Expression Profiles in LINCS L1000 CMap by Premnas

Abstract

AbstractBackgroundThe connectivity among signatures upon perturbations curated in the CMap library provides a valuable resource for understanding therapeutic pathways and biological processes associated with the drugs and diseases.MotivationHowever, due to the nature of bulk-level expression profiling by the L1000 assay, intraclonal heterogeneity and subpopulation compositional change that could contribute to the responses to perturbations are largely neglected, hampering the interpretability and reproducibility of the connections.ResultsIn this work, we proposed a computational framework, Premnas, to estimate the abundance of undetermined subpopulations from L1000 profiles in CMap directly according to an ad hoc subpopulation representation learned from a well-normalized batch of single-cell RNA-seq datasets by the archetypal analysis. By recovering the information of subpopulation changes upon perturbation, the potentials of searching for drug cocktails and drug-resistant/susceptible subpopulations with CMap L1000 were further explored and examined.ConclusionsThe proposed framework enables a new perspective to understand the connectivity among cellular signatures and expands the scope of the CMAP and other similar perturbation datasets limited by the bulk profiling technology. The executable and source code of Premnas is freely available at https://github.com/jhhung/Premnas.HighlightsA computational framework (i.e., Premnas) for learning subpopulation characteristics by the archetypal analysis and deconvoluting bulk expression profiles using the digital cytometry into subpopulation composition was proposed and validated.Intraclonal heterogeneity and subpopulation changes upon different perturbagen treatments in LINCS CMap L1000 datasets were estimated by Premnas.With Premnas, we introduced a new strategy of finding effective drug cocktails and further linked the drug-resistant subpopulation found in CMap L1000 to a known drug-resistant clone (i.e., the pre-adapted [PA] cell).To our best knowledge, this work is the first attempt to provide a new subpopulation perspective to CMap database.We believe Premnas can be applied to all the perturbation datasets, of which intraclonal/intratumoral heterogeneity was concealed by the bulk profiling and hereafter provides a new dimension of interpreting the connectivity.