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ABSTRACT: Epigenetic-focused CRISPR/Cas9 screen identifies ASH2L as a regulator of glioblastoma cell survival

PROVIDER: PRJNA828380 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21992465_1.fastq.gz	Fastqsanger.gz
	SRR21992465_2.fastq.gz	Fastqsanger.gz
	SRR21992466_1.fastq.gz	Fastqsanger.gz
	SRR21992466_2.fastq.gz	Fastqsanger.gz
	SRR21992467_1.fastq.gz	Fastqsanger.gz

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Epigenetic-focused CRISPR/Cas9 screen identifies ASH2L as a regulator of glioblastoma cell survival

Project description:Epigenetic-focused CRISPR/Cas9 screen identifies ASH2L as a regulator of glioblastoma cell survival

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Epigenetic-focused CRISPR/Cas9 screen identifies ASH2L as a regulator of glioblastoma cell survival

Project description:Glioblastoma is the most common and aggressive primary brain tumor with dismal prognosis, highlighting an urgent need for novel treatment strategies. In this study, we investigated epigenetic regulators of glioblastoma cell survival through CRISPR/Cas9 based genetic ablation screens using our customized sgRNA library EpiDoKOL, which targets critical functional domains of chromatin modifiers. Screens conducted in multiple cell lines revealed ASH2L, a histone lysine methyltransferase complex subunit, as a major regulator of glioblastoma cell viability. ASH2L depletion led to cell cycle arrest and apoptosis. RNA sequencing and Cut&Run sequencing together identified a set of cell cycle regulatory genes, such as TRA2B, BARD1, KIF20B, ARID4A, SMARCC1 that were downregulated upon ASH2L depletion. Mass spectrometry analysis demonstrated the interaction partners of ASH2L in glioblastoma cell lines as COMPASS family members including SETD1A, SETD1B, MLL1 and MLL2, however glioblastoma cells had differential dependency to COMPASS members for survival. The growth of ASH2L-depleted glioblastoma cells was markedly slower than controls in orthotopic in vivo models. TCGA analysis showed high ASH2L expression in glioblastoma compared to low grade gliomas and immunohistochemical analysis revealed significant ASH2L expression in glioblastoma tissues, attesting to its clinical relevance. Therefore, high throughput, robust and affordable screens with focused libraries, such as EpiDoKOL, holds great promise to enable rapid discovery of novel epigenetic regulators of cancer cell survival, such as ASH2L. Together, we suggest that targeting ASH2L could serve as a new therapeutic opportunity for glioblastoma.

2023-11-13 | GSE201657 | GEO

Epigenetic-focused CRISPR-Cas9 screen identifies ASH2L as a regulator of Glioblastoma cell survival

Project description:Glioblastoma Multiforme (GBM) is the most common and aggressive primary brain tumor. Despite recent developments in surgery, chemo- and radiotherapy, a currently poor prognosis of GBM patients highlights an urgent need for novel treatment strategies. Our awareness on importance of epigenetic mechanisms for tumor initiation, progression and apoptotic response lead us to investigate epigenetic regulators of GBM survival through a genetic ablation screen. Screen with our custom library EPIDOKOL targeting functional domains of critical chromatin modifier genes, revealed multiple GBM essentiality gene candidates, most importantly ASH2L. Upon ASH2L ablation, we observed induction of apoptosis and cell cycle arrest concomitant with a set of downregulated signature genes. Massive reduction in tumor forming capacity of ASH2L depleted GBM cells as well as high ASH2L expression in GBM patients in comparison to low grade gliomas (LGG) proved essentiality of the gene for glioma cell fitness. Detection of epigenetic factors modulating tumor survival via high throughput, robust and affordable screens such as EPIDOKOL holds great promise to ultimately enable rapid discovery of novel cancer biomarkers and production of effective therapies which will increase life span and dignity of cancer patients.

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EGAS00001001519-sc-20160602 - samples

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