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A Synthetic Lethality Screen Reveals ING5 as a Genetic Dependency of Catalytically Dead Set1A/COMPASS in Mouse Embryonic Stem Cells

ABSTRACT: A Synthetic Lethality Screen Reveals ING5 as a Genetic Dependency of Catalytically Dead Set1A/COMPASS in Mouse Embryonic Stem Cells

PROVIDER: PRJNA807952 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18058100.fastq.gz	Fastqsanger.gz
	SRR18058101.fastq.gz	Fastqsanger.gz
	SRR18058102.fastq.gz	Fastqsanger.gz
	SRR18058103.fastq.gz	Fastqsanger.gz
	SRR18058104.fastq.gz	Fastqsanger.gz

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A Synthetic Lethality Screen Reveals ING5 as a Genetic Dependency of Catalytically Dead Set1A/COMPASS in Mouse Embryonic Stem Cells

Project description:Embryonic stem cells (ESCs) are defined by their ability to self-renew and the potential to differentiate into all tissues of the developing organism. We previously demonstrated that deleting the catalytic SET domain of the Set1A/COMPASS histone methyltransferase in mouse ESCs does not impair their viability or ability to self-renew, however, leads to defects in differentiation. The precise mechanisms by which Set1A executes these functions remain to be elucidated. In this study, we demonstrate that mice lacking the SET domain of Set1A are embryonic lethal at a stage that is unique from null alleles. To gain insight into Set1A function in regulating pluripotency, we conducted a CRISPR/Cas9-mediated dropout screen and identified the MOZ/MORF and HBO1 acetyltransferase complex member ING5 as a synthetic perturbation to Set1A. The loss of Ing5 in Set1AΔSET mESCs decreases the fitness of these cells; and the simultaneous loss of ING5 and in Set1AΔSET leads to upregulation of differentiation-associated genes. Taken together, our results point towards Set1A and ING5 as potential co-regulators of the self-renewal and differentiation status of ESCs.

2022-03-28 | GSE196946 | GEO

A synthetic lethality screen reveals ING5 as a genetic dependency of catalytically dead Set1A/COMPASS in mouse embryonic stem cells.

Project description:Embryonic stem cells (ESCs) are defined by their ability to self-renew and the potential to differentiate into all tissues of the developing organism. We previously demonstrated that deleting the catalytic SET domain of the Set1A/complex of proteins associated with SET1 histone methyltransferase (Set1A/COMPASS) in mouse ESCs does not impair their viability or ability to self-renew; however, it leads to defects in differentiation. The precise mechanisms by which Set1A executes these functions remain to be elucidated. In this study, we demonstrate that mice lacking the SET domain of Set1A are embryonic lethal at a stage that is unique from null alleles. To gain insight into Set1A function in regulating pluripotency, we conducted a CRISPR/Cas9-mediated dropout screen and identified the MOZ/MORF (monocytic leukaemia zinc finger protein/monocytic leukaemia zinc finger protein-related factor) and HBO1 (HAT bound to ORC1) acetyltransferase complex member ING5 as a synthetic perturbation to Set1A. The loss of Ing5 in Set1AΔSET mouse ESCs decreases the fitness of these cells, and the simultaneous loss of ING5 and in Set1AΔSET leads to up-regulation of differentiation-associated genes. Taken together, our results point toward Set1A/COMPASS and ING5 as potential coregulators of the self-renewal and differentiation status of ESCs.

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Coordinated regulation of cellular identity-associated H3K4me3 breadth by the COMPASS family

Project description:Histone H3 lysine 4 trimethylation (H3K4me3) facilitates recruitment of transcription factors and epigenetic effectors to promote transcriptional activation and ensure cellular identity. This conserved histone mark is implemented by the COMPASS (COMplex of Proteins ASsociated with Set1) family of H3K4 methyltransferases. COMPASS members Set1A and Set1B have been accredited as primary depositors of global H3K4me3 in mammalian cells. Our previous studies in mouse embryonic stem cells (ESCs) demonstrated that deleting the enzymatic SET domain of Set1A does not perturb bulk H3K4me3, indicating possible compensatory roles played by other COMPASS methyltransferases. Here, we generated a series of ESC lines harboring compounding mutations of the COMPASS enzymes. We find that Set1B is functionally redundant to Set1A in implementing H3K4me3 at highly expressed genes, while Mll2 deposits H3K4me3 at less transcriptionally active promoters. Furthermore, Set1A and Set1B are responsible for broad H3K4me3 peaks, whereas Mll2 establishes H3K4me3 with narrow breadth. Most importantly, Mll2 helps preserve global H3K4me3 levels and peak breadth. Our results illustrate the biological flexibility of such enzymes in regulating transcription in a context-dependent manner to maintain stem cell identity, which could assist our understanding of their disease liability.

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Project description:Hey3Met2 cells were stably transfected with plasmids encoding either wild-type RNASET2 or a catalytically dead form (whose cDNA has been previously mutagenized in the two CAS catalytic sites) or with the empty vector as a control. The control of ovarian tumorigenesis by RNASET2 occurs through modification of the cellular microenvironment and involvement of immunocompetent cells, thus providing evidence for specific modulations of cellular responses induced by RNASET2 that might underlay ovarian tumorigenesis. In order to get more inside on the effect of RNASET2 on the modulation of other genes, a whole genome expression has been run on Hey3Met2 cell transfected with wildtype or mutated RNASET2. Hey3Met2 human ovarian cancer cells were transfected with espression vectors encoding either wild type or catalitycally dead mutant RNASET2. Clones transfected with the empty vectors were used as negative controls. Three independent clones were used for the each type of transfected plasmid.

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Catalytically inactive Ring1B maintains near wildtype levels of gene expression in mESCs

Project description:This experiment was designed to determine the extent of gene misregulation in mESCs containing catalytically dead Ring1B in comparison to mESCs lacking Ring1B. Polyadenylated mRNA was prepared from wildtype mESCs (WT), mESCs deficient for Ring1B (KO) and mESCs cells containing catalytically dead Ring1B (I53A). Each sample is represented by 3 biological replicate hybridisations.

2015-09-20 | E-GEOD-69824 | biostudies-arrayexpress

MUC1-C ACTIVATES THE SET1A/WDR5 COMPASS COMPLEX AND H3K4 TRIMETHYLATION IN CANCER STEM CELLS

Project description:MUC1-C activates the COMPASS SET1A/WDR5 complex in integrating the induction of genes that promote chronic inflammation, pluripotency and the cancer stem cell state

2022-08-24 | GSE203055 | GEO

Histone H3K4 methylation-dependent and independent functions of Set1A/COMPASS in embryonic stem cell self-renewal and differentiation

Project description:Of the six members of the COMPASS (complex of proteins associated with Set1) family of histone H3 Lys4 (H3K4) methyltransferases identified in mammals, Set1A has been shown to be essential for early embryonic development and the maintenance of embryonic stem cell (ESC) self-renewal. Like its familial relatives, Set1A possesses a catalytic SET domain responsible for histone H3K4 methylation. Whether H3K4 methylation by Set1A/COMPASS is required for ESC maintenance and during differentiation has not yet been addressed. Here, we generated ESCs harboring the deletion of the SET domain of Set1A (Set1AΔSET); surprisingly, the Set1A SET domain is dispensable for ESC proliferation and self-renewal. The removal of the Set1A SET domain does not diminish bulk H3K4 methylation in ESCs; instead, only a subset of genomic loci exhibited reduction in H3K4me3 in Set1AΔSET cells, suggesting a role for Set1A independent of its catalytic domain in ESC self-renewal. However, Set1AΔSET ESCs are unable to undergo normal differentiation, indicating the importance of Set1A-dependent H3K4 methylation during differentiation. Our data also indicate that during differentiation, Set1A but not Mll2 functions as the H3K4 methylase on bivalent genes and is required for their expression, supporting a model for transcriptional switch between Mll2 and Set1A during the self-renewing-to-differentiation transition. Together, our study implicates a critical role for Set1A catalytic methyltransferase activity in regulating ESC differentiation but not self-renewal and suggests the existence of context-specific H3K4 methylation that regulates transcriptional outputs during ESC pluripotency.

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Hey3Met2 human ovarian cancer cells overexpressing wild type or catalytically-dead mutant RNASET2

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Catalytically inactive Ring1B maintains near wildtype levels of gene expression in mESCs

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2015-09-20 | GSE69824 | GEO

RNA sequencing data of Ing4;Ing5 compound mutant embryonic mouse hearts (ING4 and ING5 are essential for histone H3 lysine 14 acetylation and epicardial cell lineage development)

Project description:Inhibitor of growth 4 and 5 (ING4 and ING5) are chromatin-binding proteins in the KAT6A, KAT6B and KAT7 histone acetyltransferase protein complexes. Heterozygous mutations in the KAT6A or KAT6B gene cause human disorders with cardiac defects, but the contribution of their chromatin adaptor proteins to development is unknown. We found that Ing5-/- mice had isolated cardiac ventricular septal defects. ING4 and ING5 are structurally similar proteins, suggesting a degree of redundancy. Combined loss of ING4 and ING5 caused developmental arrest at embryonic day E8.5, loss of histone H3 lysine 14 acetylation (H3K14ac) and a reduction in H3K23ac levels. Ing4+/-Ing5-/- hearts showed a paucity of epicardial cells and epicardium-derived cells, failure of myocardium compaction and coronary vasculature defects, accompanied by a reduction in the expression of epicardium genes. Our findings suggest that ING4 and ING5 are essential for heart development and promote epicardium and epicardium-derived cell fates and mutation of the human ING5 gene as a possible cause of isolated ventricular septal defects.

2024-02-01 | GSE246403 | GEO

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