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

Bryce, Nicole S., Failes, Tim W., Stehn, Justine R., Baker, Karen, Zahler, Stefan, Arzhaeva, Yulia, Bischof, Leanne, Lyons, Ciaran, Dedova, Irina, Arndt, Greg M., and others. (2019) High content imaging of unbiased chemical perturbations reveals that the phenotypic plasticity of the actin cytoskeleton is constrained. Cell Systems, 9 (5). pp. 496-507. ISSN 2405-4720. (doi:10.1016/j.cels.2019.09.002) (KAR id:77329)

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Official URL: https://doi.org/10.1016/j.cels.2019.09.002

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.

Item Type:	Article
DOI/Identification number:	10.1016/j.cels.2019.09.002
Uncontrolled keywords:	actin cytoskeleton, F-actin organization, talin, talin inhibitor, attractor state, plasticity, phenotypic analysis, high content analysis, high content screening, high throughput screening
Subjects:	Q Science > QH Natural history > QH301 Biology
Divisions:	Divisions > Division of Natural Sciences > Biosciences
Funders:	Biotechnology and Biological Sciences Research Council (https://ror.org/00cwqg982) International Human Frontier Science Program Organization (https://ror.org/02ebx7v45)
Depositing User:	Ben Goult
Date Deposited:	11 Oct 2019 05:34 UTC
Last Modified:	04 Mar 2024 16:25 UTC
Resource URI:	https://kar.kent.ac.uk/id/eprint/77329 (The current URI for this page, for reference purposes)

University of Kent Author Information

Baker, Karen.

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Goult, Benjamin T..

Creator's ORCID:	https://orcid.org/0000-0002-3438-2807
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