Abstract
Motivation: Applications in synthetic and systems biology can benefit from measuring whole-cell response to biochemical perturbations. Execution of experiments to cover all possible combinations of perturbations is infeasible. In this paper, we present the host response model (HRM), a machine learning approach that maps response of single perturbations to transcriptional response of the combination of perturbations. Results: The HRM combines high-throughput sequencing with machine learning to infer links between experimental context, prior knowledge of cell regulatory networks, and RNASeq data to predict a gene's dysregulation. We find that the HRM can predict the directionality of dysregulation to a combination of inducers with an accuracy of >90% using data from single inducers. We further find that the use of prior, known cell regulatory networks doubles the predictive performance of the HRM (an R2 from 0.3 to 0.65). The model was validated in two organisms, Escherichia coli and Bacillus subtilis, using new experiments conducted after training. Finally, while the HRM is trained with gene expression data, the direct prediction of differential expression makes it possible to also conduct enrichment analyses using its predictions. We show that the HRM can accurately classify >95% of the pathway regulations. The HRM reduces the number of RNASeq experiments needed as responses can be tested in silico prior to the experiment.
Original language | English |
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Pages (from-to) | 404-409 |
Number of pages | 6 |
Journal | Bioinformatics |
Volume | 38 |
Issue number | 2 |
DOIs | |
State | Published - 3 Jan 2022 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2021 The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected].
Funding
This material is based upon work supported by the Defense Advanced Research Projects Agency (DARPA) and the Air Force Research Laboratory under Contract No. FA8750-17-C- 0231.
Funders | Funder number |
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Defense Advanced Research Projects Agency | |
Air Force Research Laboratory | FA8750-17-C- 0231 |