A map of directional genetic interactions in a metazoan cell

ELife
Bernd FischerMichael Boutros

Abstract

Gene-gene interactions shape complex phenotypes and modify the effects of mutations during development and disease. The effects of statistical gene-gene interactions on phenotypes have been used to assign genes to functional modules. However, directional, epistatic interactions, which reflect regulatory relationships between genes, have been challenging to map at large-scale. Here, we used combinatorial RNA interference and automated single-cell phenotyping to generate a large genetic interaction map for 21 phenotypic features of Drosophila cells. We devised a method that combines genetic interactions on multiple phenotypes to reveal directional relationships. This network reconstructed the sequence of protein activities in mitosis. Moreover, it revealed that the Ras pathway interacts with the SWI/SNF chromatin-remodelling complex, an interaction that we show is conserved in human cancer cells. Our study presents a powerful approach for reconstructing directional regulatory networks and provides a resource for the interpretation of functional consequences of genetic alterations.

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Citations

Dec 3, 2015·Critical Reviews in Biochemistry and Molecular Biology·Tianzuo Zhan, Michael Boutros
Dec 8, 2015·Cell·Michael BoutrosChristina Laufer
May 23, 2015·Molecular Cell·Nevan J KroganTrey Ideker
Apr 19, 2016·Current Opinion in Biotechnology·Juan C CaicedoAnne E Carpenter
Apr 28, 2016·Trends in Cell Biology·Mojca Mattiazzi UsajBrenda J Andrews
May 7, 2016·Bioinformatics·Ivan H GoenawanDavid J Lynn
Mar 21, 2017·ELife·Mohammad Hossein RohbanAnne E Carpenter
Jun 20, 2017·Journal of Biotechnology·Benedikt RauscherMichael Boutros
Nov 7, 2015·Molecular Biology of the Cell·Yoshikazu OhyaShinsuke Ohnuki
May 10, 2017·Nature Methods·Dan DuNevan J Krogan
Sep 1, 2017·Nature Methods·Juan C CaicedoAnne E Carpenter
Jan 16, 2018·Nature Biotechnology·Michael BoettcherMichael T McManus
Feb 23, 2018·Molecular Systems Biology·Benedikt RauscherMichael Boutros
May 17, 2017·BMC Genetics·Marta K LabochaWeiwei Zhong
Feb 19, 2017·Molecular Cancer·Yanyan TangZhaoyang Zeng
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Jan 13, 2017·Cell Division·Maximilian Billmann, Michael Boutros
Mar 1, 2018·Genetics·Florian HeigwerMichael Boutros
Dec 17, 2017·Cancer Metastasis Reviews·Tony GutschnerMartin Pichler
Dec 24, 2020·Nature Reviews. Drug Discovery·Srinivas Niranj ChandrasekaranAnne E Carpenter
Jul 24, 2018·Cell·Max A HorlbeckLuke A Gilbert
May 24, 2021·Current Opinion in Chemical Biology·Aditya PratapaJuan C Caicedo

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Methods Mentioned

BETA
gene knockdown
GTPase
dissection
PCR
in vitro transcription
FCS
Assay

Software Mentioned

BLAST
R package EBImage
NEXT
R package limma
RNAi

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