Combinatorial CRISPR screen identifies fitness effects of gene paralogues

Thompson, Nicola; Ranzani, Marco; Weyden, Louise van der; Iyer, Vivek; Offord, Victoria; Droop, Alastair; Behan, Fiona M.; Gonçalvès, Emanuel; Speak, Anneliese O.; Iorio, Francesco; Hewinson, James; Harle, Victoria; Robertson, Holly; Anderson, Elizabeth; Fu, Beiyuan; Yang, Fengtang; Zagnoli-Vieira, Guido; Chapman, Phil; Velasco-Herrera, Martín Del Castillo; Garnett, Mathew J.; Jackson, Stephen; Adams, David J.

doi:10.1038/s41467-021-21478-9

Cited by 67 publications

(60 citation statements)

References 49 publications

(45 reference statements)

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“…In addition, PaCT also identified several paralog dependencies that have recently been described, including SMARCA2-SMARCA4 or SLC25A28-SLC25A37 19 . We used CRISPR GFP-depletion assays to experimentally validate the genetic dependencies on FAM50A in cells where FAM50B expression is low, and on VPS4A in VPS4B -low cell lines (Figure 3c,d and Supplementary Figure 3g,h), two paralog interactions that have recently been functionally characterized 19,52,53 .…”

Section: Resultsmentioning

confidence: 73%

“…In contrast to other recent paralog studies, we did not limit the PaCT search space to paralog pairs by a similarity cutoff or membership in a paralog gene family of a given (small) size 13,19 . An additional advantage of PaCT is the ability to identify candidate interaction partners for genes that have not been targeted themselves as queries, as long as expression data are available for them to act as biomarkers.…”

Section: Resultsmentioning

confidence: 99%

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Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sex chromosome encoded genes

Köferle

Schlattl

Hörmann

et al. 2021

Preprint

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Genetic networks are characterized by extensive buffering. During tumour evolution, disruption of these functional redundancies can create de novo vulnerabilities that are specific to cancer cells. In this regard, paralog genes are of particular interest, as the loss of one paralog gene can render tumour cells dependent on a remaining paralog. To systematically identify cancer-relevant paralog dependencies, we searched for candidate dependencies using CRISPR screens and publicly available loss-of-function datasets. Our analysis revealed >2,000 potential candidate dependencies, several of which were subsequently experimentally validated. We provide evidence that DNAJC15-DNAJC19, FAM50A-FAM50B and RPP25-RPP25L are novel cancer relevant paralog dependencies. Importantly, our analysis also revealed unexpected redundancies between sex chromosome genes. We show that chrX- and chrY- encoded paralogs, as exemplified by ZFX-ZFY, DDX3X-DDX3Y and EIF1AX-EIF1AY, are functionally linked so that tumour cell lines from male patients with Y-chromosome loss become exquisitely dependent on the chrX-encoded gene. We therefore propose genetic redundancies between chrX- and chrY- encoded paralogs as a general therapeutic strategy for human tumours that have lost the Y-chromosome.

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Section: Resultsmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sex chromosome encoded genes

Köferle

Schlattl

Hörmann

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Consistent with our C-score prediction, the FAM50A-FAM50B gene pair in the A549 and MCF7 cell lines exhibited stronger synergy than in the U2OS cell line (Bliss score: 1.07 in A549, 1.06 in MCF7 and 1.44 in U2OS). Note that a recently study showed synthetic lethality between FAM50A and FAM50B in the A375 cell line [21], which is also located at the top-right of the FAM50A-FAM50B C-score plot (Fig. 3A).…”

Section: Experimental Validation Of C-score-inferred Cell-specific Expression Bufferingmentioning

confidence: 61%

Functional buffering via cell-specific gene expression promotes tissue homeostasis and cancer robustness

Lin

Cheng

et al. 2021

Preprint

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Functional buffering ensures biological robustness critical for cell survival and physiological homeostasis in response to environmental challenges. However, in multicellular organisms, the mechanism underlying cell- and tissue-specific buffering and its implications for cancer development remain elusive. Here, we propose a Cell-specific Expression-BUffering (CEBU) mechanism, whereby a gene's function is buffered by cell-specific expression of a buffering gene, to describe functional buffering in humans. The likelihood of CEBU between gene pairs is quantified using a C-score index. By computing C-scores using genome-wide CRISPR screens and transcriptomic RNA-seq of 684 human cell lines, we report that C-score-identified putative buffering gene pairs are enriched for members of the same pathway, protein complex and duplicated gene family. Furthermore, these buffering gene pairs contribute to cell-specific genetic interactions and are indicative of tissue-specific robustness. C-score derived buffering capacities can help predict patient survival in multiple cancers. Our results reveal CEBU as a critical mechanism of functional buffering contributing to cell survival and cancer robustness in humans.

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“…There is also a CRISPR strategy designed to target fusion oncogenes through targeting of two intronic sequences, one from each gene in the fusion oncogene, without affecting the genes in germline non-rearranged alleles (Martinez-Lage et al, 2020). Combinatorial CRISPR screens are increasingly being used to identify synthetic lethal targets (Thompson et al, 2021). Zhou and colleagues demonstrate the efficient knockout of three genes simultaneously in a human ovarian cancer cell line, to illustrate their technology can be applied to screen for synergistic anti-cancer genetic combinations (Zhou et al, 2020).…”

Section: Rnai and Crispr Screensmentioning

confidence: 99%

Functional genomics approaches to improve pre‐clinical drug screening and biomarker discovery

Nguyen

Caldas

2021

EMBO Mol Med

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Advances in sequencing technology have enabled the genomic and transcriptomic characterization of human malignancies with unprecedented detail. However, this wealth of information has been slow to translate into clinically meaningful outcomes. Different models to study human cancers have been established and extensively characterized. Using these models, functional genomic screens and pre-clinical drug screening platforms have identified genetic dependencies that can be exploited with drug therapy. These genetic dependencies can also be used as biomarkers to predict response to treatment. For many cancers, the identification of such biomarkers remains elusive. In this review, we discuss the development and characterization of models used to study human cancers, RNA interference and CRISPR screens to identify genetic dependencies, large-scale pharmacogenomics studies and drug screening approaches to improve pre-clinical drug screening and biomarker discovery.

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Combinatorial CRISPR screen identifies fitness effects of gene paralogues

Cited by 67 publications

References 49 publications

Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sex chromosome encoded genes

Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sex chromosome encoded genes

Functional buffering via cell-specific gene expression promotes tissue homeostasis and cancer robustness

Functional genomics approaches to improve pre‐clinical drug screening and biomarker discovery

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