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Integrative multiomic approaches reveal ZMAT3 and p21 as conserved hubs in the p53 tumor suppression network

ABSTRACT: Integrative multiomic approaches reveal ZMAT3 and p21 as conserved hubs in the p53 tumor suppression network

PROVIDER: PRJNA1223182 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32328524_1.fastq.gz	Fastqsanger.gz
	SRR32328524_2.fastq.gz	Fastqsanger.gz
	SRR32328525_1.fastq.gz	Fastqsanger.gz
	SRR32328525_2.fastq.gz	Fastqsanger.gz
	SRR32328526_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Integrative multiomic approaches reveal ZMAT3 and p21 as conserved hubs in the p53 tumor suppression network

Project description:TP53, the most frequently mutated gene in human cancer, encodes a transcriptional activator that induces myriad downstream target genes. Despite the importance of p53 in tumor suppression, the specific p53 target genes important for tumor suppression remain unclear. Recent studies have identified the p53-inducible gene Zmat3 as a critical effector of tumor suppression, but many questions remain regarding its p53-dependence, activity across contexts, and mechanism of tumor suppression alone and in cooperation with other p53-inducible genes. To address these questions, we used Tuba-seqUltra somatic genome editing and tumor barcoding in a mouse lung adenocarcinoma model, combinatorial in vivo CRISPR/Cas9 screens, meta-analyses of gene expression and Cancer Dependency Map data, and integrative RNA-sequencing and shotgun proteomic analyses. We established Zmat3 as a core component of p53-mediated tumor suppression and identified Cdkn1a as the most potent cooperating p53-induced gene in tumor suppression. We discovered that ZMAT3/CDKN1A serve as near-universal effectors of p53-mediated tumor suppression that regulate cell division, migration, and extracellular matrix organization. Accordingly, combined Zmat3-Cdkn1a inactivation dramatically enhanced cell proliferation and migration compared to controls, akin to p53 inactivation. Together, our findings place ZMAT3 and CDKN1A as hubs of a p53-induced gene program that opposes tumorigenesis across various cellular and genetic contexts.

2025-02-21 | GSE289471 | GEO

Combined absence of Trp53 target genes Zmat3, Puma and p21 cause a high incidence of cancer in mice

Project description:Transcriptional activation of target genes is essential for TP53-mediated tumour suppression, though the roles of the diverse TP53-activated target genes in tumour suppression remains poorly understood. Knockdown of Zmat3, an RNA-binding zinc-finger protein involved in regulating alternative splicing, in haematopoietic cells by shRNA caused leukaemia only with the concomitant absence of the Puma and p21, the critical effectors of Trp53-mediated apoptosis and cell cycle arrest respectively. We were interested to further investigate the role of ZMAT3 in tumour suppression beyond the haematopoietic system. Therefore, we generated Zmat3 knockout and compound gene knockout mice, lacking Zmat3 and p21, Zmat3 and Puma or all three genes. Puma-/-p21-/-Zmat3-/- triple knockout mice developed tumours at a significantly higher frequency compared to wild-type, Puma-/-Zmat3-/- or p21-/-Zmat3-/-deficient mice. Interestingly, we observed that the triple knockout and Puma-/-Zmat3-/- double deficient animals succumbed to lymphoma, while p21-/-Zmat3-/- animals developed mainly solid cancers. This analysis suggests that in addition to ZMAT3 loss, additional TRP53-regulated processes must be disabled simultaneously for TRP53-mediated tumour suppression to fail. Our findings reveal that the absence of different TRP53 regulated tumour suppressive processes changes the tumour spectrum, indicating that different TRP53 tumour suppressive pathways are more critical in different tissues.

2023-11-28 | GSE248747 | GEO

Identifying Zmat3-bound RNAs

Project description:The goal of the study was to identify RNAs bound by Zmat3 using eCLIP.

2020-11-06 | GSE145555 | GEO

Identifying Zmat3-bound RNAs

Project description:Identifying Zmat3-bound RNAs

| PRJNA607540 | ENA

Identifying differentially expressed genes in Zmat3 knockout cells

Project description:The goal of the study was to identify genes whose expression is Zmat3 depedent using RNA-seq.

2020-11-06 | GSE145430 | GEO

p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC [PAR-CLIP_ZMAT3]

Project description:Purpose: p53 is a well-studied protein in which the activation of its main targets is not enough to explain its tumor suppressor effect. Aiming to search for direct p53 targets that mediate less studied processes within p53 pathway, like post-transcriptional regulation, we selected ZMAT3 as the RNA-binding protein most upregulated by p53 activation. Methods: We investigated ZMAT3 targets by using PAR-CLIP and RNA-seq in colorectal cancer cell line HCT116. Results: We found that ZMAT3 binds to ~5000 genes mainly in their introns. It also causes alternative splicing and CD44 was its mostly altered target. ZMAT3 knock-down increased CD44v2-v10 and CD44v3-v10, but decreased CD44s expression. Increased survival and clonogenicity was observed upon knock-down of ZMAT3, which was rescued upon concurrent knock-down of CD44v Conclusions: We propose that ZMAT3 regulates splicing of CD44 following activation by p53, which upregulates CD44s at the expense of CD44v isoforms and leads to a decrease tumorigenicity.

2020-12-18 | GSE150715 | GEO

p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC [RNA-seq_ZMAT3]

Project description:Purpose: p53 is a well-studied protein in which the activation of its main targets is not enough to explain its tumor suppressor effect. Aiming to search for direct p53 targets that mediate less studied processes within p53 pathway, like post-transcriptional regulation, we selected ZMAT3 as the RNA-binding protein most upregulated by p53 activation. Methods: We investigated ZMAT3 targets by using PAR-CLIP and RNA-seq in colorectal cancer cell line HCT116. Results.txt: We found that ZMAT3 binds to ~5000 genes mainly in their introns. It also causes alternative splicing and CD44 was its mostly altered target. ZMAT3 knock-down increased CD44v2-v10 and CD44v3-v10, but decreased CD44s expression. Increased survival and clonogenicity was observed upon knock-down of ZMAT3, which was rescued upon concurrent knock-down of CD44v Conclusions: We propose that ZMAT3 regulates splicing of CD44 following activation by p53, which upregulates CD44s at the expense of CD44v isoforms and leads to a decrease tumorigenicity.

2020-12-18 | GSE150717 | GEO

p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC [RNA-seq_UPF1]

Project description:Purpose: p53 is a well-studied protein in which the activation of its main targets is not enough to explain its tumor suppressor effect. Aiming to search for direct p53 targets that mediate less studied processes within p53 pathway, like post-transcriptional regulation, we selected ZMAT3 as the RNA-binding protein most upregulated by p53 activation. Methods: We investigated ZMAT3 targets by using PAR-CLIP and RNA-seq in colorectal cancer cell line HCT116. Results.txt: We found that ZMAT3 binds to ~5000 genes mainly in their introns. It also causes alternative splicing and CD44 was its mostly altered target. ZMAT3 knock-down increased CD44v2-v10 and CD44v3-v10, but decreased CD44s expression. Increased survival and clonogenicity was observed upon knock-down of ZMAT3, which was rescued upon concurrent knock-down of CD44v Conclusions: We propose that ZMAT3 regulates splicing of CD44 following activation by p53, which upregulates CD44s at the expense of CD44v isoforms and leads to a decrease tumorigenicity.

2020-12-18 | GSE150716 | GEO

Identifying differentially expressed genes in Zmat3 knockout cells

Project description:Identifying differentially expressed genes in Zmat3 knockout cells

| PRJNA607207 | ENA

Effect of CDK8/19 inhibitor Senexin A on p21-regulated gene expression in human HT1080 p21-9 cells with IPTG-inducible p21

Project description:p21 (CDKN1A) expression from an IPTG-inducible promoter in HT1080 p21-9 cells was previously shown to inhibit a set of genes, many of which are involved in cell cycle progression, and to upregulate another set of genes, some of which have been implicated in cancer and age-related diseases. We have now developed Senexin A, a small-molecule inhibitor of p21-induced transcription, which we found to be a selective inhibitor of CDK8 and CDK19. Here we tested the effect of Senexin A on the induction and inhibition of transcription by p21. In this dataset, we include microarray gene expression data from samples of HT1080 p21-9 cells that were either untreated, treated with p21-inducing IPTG alone, with Senexin A alone, or with IPTG and Senexin A. This experiment shows that Senexin A inhibits primarily the induction but not the inhibition of gene expression by p21. The data for each of the four samples were normalized to the sample from untreated cells, using GeneSpring GX. Fold changes in gene expression upon the addition of IPTG with or without Senexin A were compared using Microsft Excel. Changes in the expression of specific GO categories of genes were compared using GeneSpring.

2012-08-12 | E-GEOD-39464 | biostudies-arrayexpress

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