High-content imaging of unbiased chemical perturbations reveals that the phenotypic plasticity of the actin cytoskeleton is constrained

Nicole S. Bryce, Tim W. Failes, Justine R. Stehn, Karen Baker, Stefan Zahler, Yulia Arzhaeva, Leanne Bischof, Ciaran Lyons, Irina Dedova, Greg M. Arndt, Katharina Gaus, Benjamin T. Goult, Edna C. Hardeman, Peter W. Gunning, John G. Lock*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Although F-actin has a large number of binding partners and regulators, the number of phenotypic states available to the actin cytoskeleton is unknown. Here, we quantified 74 features defining filamentous actin (F-actin) and cellular morphology in >25 million cells after treatment with a library of 114,400 structurally diverse compounds. After reducing the dimensionality of these data, only ∼25 recurrent F-actin phenotypes emerged, each defined by distinct quantitative features that could be machine learned. We identified 2,003 unknown compounds as inducers of actin-related phenotypes, including two that directly bind the focal adhesion protein, talin. Moreover, we observed that compounds with distinct molecular mechanisms could induce equivalent phenotypes and that initially divergent cellular responses could converge over time. These findings suggest a conceptual parallel between the actin cytoskeleton and gene regulatory networks, where the theoretical plasticity of interactions is nearly infinite, yet phenotypes in vivo are constrained into a limited subset of practicable configurations.

Original languageEnglish
Pages (from-to)496-507
Number of pages17
JournalCell Systems
Volume9
Issue number5
DOIs
Publication statusPublished - 27 Nov 2019
Externally publishedYes

Keywords

  • actin cytoskeleton
  • attractor state
  • F-actin organization
  • high content analysis
  • high content screening
  • high throughput screening
  • phenotypic analysis
  • plasticity
  • talin
  • talin inhibitor

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