Pan-cancer multi-omics analysis and orthogonal experimental assessment of epigenetic driver genes

Halaburkova, Andrea; Cahais, Vincent; Novoloaca, Alexei; Araujo, Mariana Gomes da Silva; Khoueiry, Rita; Ghantous, Akram; Herceg, Zdenko

doi:10.1101/gr.268292.120

Cited by 24 publications

(28 citation statements)

References 34 publications

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“…Since KATs can also acetylate non-histone proteins, it will be important to dissect out the mechanisms by which KAT8 regulates TNBC cell fitness to be able to precisely target this complex in breast cancer. Interestingly, previously published epigenome-wide libraries did not include KANSL2, KANSL3 and SS18L2 targeting sgRNAs, and therefore failed to identify strong effects of these genes on cell survival [44][45][46]. Therefore, the broad targeted gene list of EPIKOL ensures identification of true-positive hits.…”

Section: Discussionmentioning

confidence: 99%

“…Successful validation of individual candidate genes through follow-up competition and cell growth assays showed that EPIKOL is suitable to functionally interrogate a wide range of epigenetic modifiers. In contrast to most currently available epigenome-focused libraries, which only target chromatin modifiers such as writers, readers and erasers [44][45][46], EPIKOL targets a wider range of genes coding for chromatin complex cofactors and structural components [48]. Thus, its use will likely lead to a broader understanding of the functions of these complexes as a whole.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we present our focused Epigenetic Knock-out Library (EPIKOL), which targets a broader range of epigenetic modifiers and consists of more sgRNAs for each gene when compared to previously published libraries [44][45][46]. Utilizing this epigenome wide library in screens of two different cancer types, we revealed novel epigenetic modifiers that regulate cancer cell fitness.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, focused libraries may be advantageous in experimental systems that require clinically relevant models such as primary cells, patient-derived xenografts [37] or in vivo models [38][39][40]. To date, various focused libraries have been generated targeting microRNAs [41], kinases [42,43], nuclear proteins [37], epigenetic modifiers [44][45][46] or genes belonging to a certain pathway such as DNAdamage response [47].…”

Section: Introductionmentioning

confidence: 99%

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EPIKOL, a chromatin-focused CRISPR/Cas9-based screening platform, to identify cancer-specific epigenetic vulnerabilities

Yedier-Bayram

Gokbayrak

Aksu

et al. 2021

Preprint

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Dysregulation of the epigenome due to alterations in chromatin modifier proteins commonly contribute to malignant transformation. To discover new drug targets for more targeted and personalized therapies, functional interrogation of epigenetic modifiers is essential. We therefore generated an epigenome-wide CRISPR-Cas9 knock-out library (EPIKOL) that targets a wide-range of epigenetic modifiers and their cofactors. We conducted eight screens in two different cancer types and showed that EPIKOL performs with high efficiency in terms of sgRNA distribution, depletion of essential genes and steady behaviors of non-targeting sgRNAs. From this, we discovered novel epigenetic modifiers besides previously known ones that regulate triple-negative breast cancer and prostate cancer cell fitness. With further validation assays, we confirmed the growth-regulatory function of individual candidates, including SS18L2 and members of the NSL complex (KANSL2, KANSL3, KAT8) in triple negative breast cancer cells. Overall, we show that EPIKOL, a focused sgRNA library targeting approximately 800 genes, can reveal epigenetic modifiers that are essential for cancer cell fitness and serve as a tool to offer novel anti-cancer targets. With its thoroughly generated epigenome-wide gene list, and the relatively high number of sgRNAs per gene, EPIKOL offers a great advantage to study functional roles of epigenetic modifiers in a wide variety of research applications, such as screens on primary cells, patient-derived xenografts as well as in vivo models.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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EPIKOL, a chromatin-focused CRISPR/Cas9-based screening platform, to identify cancer-specific epigenetic vulnerabilities

Yedier-Bayram

Gokbayrak

Aksu

et al. 2021

Preprint

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“…Due to the enhancement of omics approaches and strategies for multi-omics data integration over the last years, we believe that this needs to be changed in the future. Thereby, not only the integration of transcriptome, proteome, and metabolome but also of further omics layers, e.g., epigenome [ 176 ], methylome [ 177 ], acetylome [ 178 ], and phosphoproteome [ 179 ], should be considered. Post-translational modifications (PTMs) are highly relevant since they regulate protein function, activity and thus, cell signaling [ 180 ].…”

Section: Discussionmentioning

confidence: 99%

Systematic Review of Multi-Omics Approaches to Investigate Toxicological Effects in Macrophages

Karkossa

Raps

Bergen

et al. 2020

IJMS

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Insights into the modes of action (MoAs) of xenobiotics are of utmost importance for the definition of adverse outcome pathways (AOPs), which are essential for a mechanism-based risk assessment. A well-established strategy to reveal MoAs of xenobiotics is the use of omics. However, often an even more comprehensive approach is needed, which can be achieved using multi-omics. Since the immune system plays a central role in the defense against foreign substances and pathogens, with the innate immune system building a first barrier, we systematically reviewed multi-omics studies investigating the effects of xenobiotics on macrophages. Surprisingly, only nine publications were identified, combining proteomics with transcriptomics or metabolomics. We summarized pathways and single proteins, transcripts, or metabolites, which were described to be affected upon treatment with xenobiotics in the reviewed studies, thus revealing a broad range of effects. In summary, we show that macrophages are a relevant model system to investigate the toxicological effects induced by xenobiotics. Furthermore, the multi-omics approaches led to a more comprehensive overview compared to only one omics layer with slight advantages for combinations that complement each other directly, e.g., proteome and metabolome.

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Mechanisms of Histone Modifications

Vanzan¹,

Sklias²,

Bošković³

et al. 2023

Handbook of Epigenetics

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Pan-cancer multi-omics analysis and orthogonal experimental assessment of epigenetic driver genes

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Cited by 24 publications

References 34 publications

EPIKOL, a chromatin-focused CRISPR/Cas9-based screening platform, to identify cancer-specific epigenetic vulnerabilities

EPIKOL, a chromatin-focused CRISPR/Cas9-based screening platform, to identify cancer-specific epigenetic vulnerabilities

Systematic Review of Multi-Omics Approaches to Investigate Toxicological Effects in Macrophages

Mechanisms of Histone Modifications

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