Processes in DNA damage response from a whole-cell multi-omics perspective

James C Pino; Alexander L R Lubbock; Leonard A Harris; Danielle B Gutierrez; Melissa A Farrow; Nicole Muszynski; Tina Tsui; Stacy D Sherrod; Jeremy L Norris; John A McLean; Richard M Caprioli; John P Wikswo; Carlos F Lopez

doi:10.1016/j.isci.2022.105341

Processes in DNA damage response from a whole-cell multi-omics perspective

iScience. 2022 Oct 19;25(11):105341. doi: 10.1016/j.isci.2022.105341. eCollection 2022 Nov 18.

Authors

James C Pino^{1

2

3}, Alexander L R Lubbock^{2

4}, Leonard A Harris^{5

6

7}, Danielle B Gutierrez², Melissa A Farrow⁸, Nicole Muszynski⁹, Tina Tsui², Stacy D Sherrod^{4

10

11}, Jeremy L Norris^{2

10}, John A McLean^{4

10

11}, Richard M Caprioli^{2

10

12

13}, John P Wikswo^{9

14

15

16}, Carlos F Lopez^{2

4

17

3}

Affiliations

¹ Chemical and Physical Biology Graduate Program, Vanderbilt University, Nashville, TN, USA.
² Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
³ Pacific Northwest National Laboratory, Seattle, WA, USA.
⁴ Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵ Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA.
⁶ Interdisciplinary Graduate Program in Cell & Molecular Biology, University of Arkansas, Fayetteville, AR, USA.
⁷ Cancer Biology Program, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
⁸ Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁹ Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
¹⁰ Department of Chemistry, Vanderbilt University, Nashville, TN, USA.
¹¹ Center for Innovative Technology (CIT), Vanderbilt University, Nashville, TN, USA.
¹² Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
¹³ Department of Medicine, Vanderbilt University, Nashville, TN, USA.
¹⁴ Department of Physics and Astronomy, Vanderbilt University, Nashville, TN, USA.
¹⁵ Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
¹⁶ Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, TN, USA.
¹⁷ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.

Abstract

Technological advances have made it feasible to collect multi-condition multi-omic time courses of cellular response to perturbation, but the complexity of these datasets impedes discovery due to challenges in data management, analysis, visualization, and interpretation. Here, we report a whole-cell mechanistic analysis of HL-60 cellular response to bendamustine. We integrate both enrichment and network analysis to show the progression of DNA damage and programmed cell death over time in molecular, pathway, and process-level detail using an interactive analysis framework for multi-omics data. Our framework, Mechanism of Action Generator Involving Network analysis (MAGINE), automates network construction and enrichment analysis across multiple samples and platforms, which can be integrated into our annotated gene-set network to combine the strengths of networks and ontology-driven analysis. Taken together, our work demonstrates how multi-omics integration can be used to explore signaling processes at various resolutions and demonstrates multi-pathway involvement beyond the canonical bendamustine mechanism.

Keywords: Bioinformatics; Complex system biology; Data processing in systems biology; Systems biology.