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Zinc finger protein 280C contributes to colorectal tumorigenesis by maintaining epigenetic repression at H3K27me3-marked loci

ABSTRACT: Zinc finger protein 280C contributes to colorectal tumorigenesis by maintaining epigenetic repression at H3K27me3-marked loci

PROVIDER: PRJNA753705 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15326610.fastq.gz	Fastqsanger.gz
	SRR15326611.fastq.gz	Fastqsanger.gz
	SRR15326612.fastq.gz	Fastqsanger.gz
	SRR15326613.fastq.gz	Fastqsanger.gz
	SRR15326614.fastq.gz	Fastqsanger.gz

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Zinc finger protein 280C contributes to colorectal tumorigenesis by maintaining epigenetic repression at H3K27me3-marked loci.

Project description:Dysregulated epigenetic and transcriptional programming due to abnormalities of transcription factors (TFs) contributes to and sustains the oncogenicity of cancer cells. Here, we unveiled the role of zinc finger protein 280C (ZNF280C), a known DNA damage response protein, as a tumorigenic TF in colorectal cancer (CRC), required for colitis-associated carcinogenesis and Apc deficiency–driven intestinal tumorigenesis in mice. Consistently, ZNF280C silencing in human CRC cells inhibited proliferation, clonogenicity, migration, xenograft growth, and liver metastasis. As a C2H2 (Cys2-His2) zinc finger-containing TF, ZNF280C occupied genomic intervals with both transcriptionally active and repressive states and coincided with CCCTC-binding factor (CTCF) and cohesin binding. Notably, ZNF280C was crucial for the repression program of trimethylation of histone H3 at lysine 27 (H3K27me3)-marked genes and the maintenance of both focal and broad H3K27me3 levels. Mechanistically, ZNF280C counteracted CTCF/cohesin activities and condensed the chromatin environment at the cis elements of certain tumor suppressor genes marked by H3K27me3, at least partially through recruiting the epigenetic repressor structural maintenance of chromosomes flexible hinge domain-containing 1 (SMCHD1). In clinical relevance, ZNF280C was highly expressed in primary CRCs and distant metastases, and a higher ZNF280C level independently predicted worse prognosis of CRC patients. Thus, our study uncovered a contributor with good prognostic value to CRC pathogenesis and also elucidated the essence of DNA-binding TFs in orchestrating the epigenetic programming of gene regulation.

| S-EPMC9295756 | biostudies-literature

Zinc finger protein 280C contributes to colorectal tumorigenesis by maintaining epigenetic repression at H3K27me3-marked loci

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-05-19 | GSE181856 | GEO

Multiparameter functional diversity of human C2H2 zinc finger proteins [RNA-Seq]

Project description:C2H2 zinc finger proteins represent the largest and most enigmatic class of human transcription factors. Their C2H2 arrays are highly variable, indicating that most will have unique DNA binding motifs. However, most of the binding motifs have not been directly determined. We have determined the binding sites and motifs of 119 C2H2 zinc finger proteins and the expression pattern of 80 cell lines overexpressing C2H2 zinc finger proteins in order to study the role of C2H2 zinc finger proteins in gene regulation. We expressed GFP-tagged C2H2-ZF proteins in stable transgenic HEK293 cells. Total RNA was isolated using Trizol and sequencing libraries were constructed using TruSeq Stranded Total RNA Library Prep Kit with Ribo-Zero Gold or TruSeq RNA Library Preparation Kit v2.

2016-10-25 | E-GEOD-76495 | biostudies-arrayexpress

Multiparameter functional diversity of human C2H2 zinc finger proteins [RNA-Seq]

2016-10-25 | GSE76495 | GEO

Off-Target Analysis of Zinc Finger Nucleases

Project description:Zinc Finger Nucleases (ZFNs) facilitate precise editing of DNA enabling targeted genomic modifications in vivo. ZFNs have been employed to obtain genetically modified plants and animals, and cell-based therapies utilizing ZFNs are undergoing clinical trials. However, many ZFNs display dose-dependent toxicity presumably due to the generation of undesired double stranded breaks at off-target sites within the genome. To evaluate the parameters influencing the functional specificity of ZFNs, we compared the in vivo activity of ZFN variants targeting the zebrafish kdrl locus, which display both high on-target activity and dose-dependent toxicity. We evaluated their functional specificity by assessing lesion frequency at 141 potential off-target sites within the zebrafish genome using Illumina sequencing. Only a minority of these off-target sites displayed significant lesion frequency with kdrl ZFNs. Furthermore, we find that active off-target sites appear to be defined by the thermodynamics of zinc finger-DNA recognition. Surprisingly, we observed that the zinc finger protein specificity and the choice of the engineered dimerization domain of the FokI nuclease could independently influence the fidelity of these ZFNs. The results of this study have implications for the assessment of likely off-target sites within a genome and point to both ZFP-dependent and –independent mechanisms of potential improvement for engineering ZFNs with higher levels of precision. Examined lesions at 141 off-target sites for various treatments of ZFNs and compare to the untreated sample stage 1: raw read but missing quality values stage 2: fastq files available from SRA

2010-08-25 | E-GEOD-23762 | biostudies-arrayexpress

Targeting transcription factors through an IMiD independent zinc finger domain

Project description:Immunomodulatory imide drugs (IMiDs) degrade specific C2H2 zinc finger degrons in transcription factors, making them effective against certain cancers. SALL4, a cancer driver, contains seven C2H2 zinc fingers in three clusters, including an IMiD degron in zinc finger cluster one (ZFC1). Surprisingly, IMiDs do not inhibit the growth of SALL4-expressing cancer cells. To overcome this limit, we focused on a non-IMiD domain, SALL4 zinc finger cluster four (ZFC4). By combining ZFC4-DNA crystal structure and an in silico docking algorithm, in conjunction with cell viability assays, we screened several chemical libraries against a potentially druggable binding pocket, leading to the discovery of SH6, a compound that selectively targets SALL4-expressing cancer cells. Mechanistic studies revealed that SH6 degrades SALL4 protein through the CUL4A/CRBN pathway, while deletion of ZFC4 abolished this activity. Moreover, SH6 treatment led to a significant 87% tumor growth inhibition of SALL4+ patient-derived xenografts and demonstrated good bioavailability in pharmacokinetic studies. In summary, these studies represent a new approach for IMiD independent drug discovery targeting C2H2 transcription factors such as SALL4 in cancer.

2025-06-23 | PXD061151 | Pride

Dependence of gene regulation by prostaglandin A1 on a zinc finger protein

Project description:A zinc finger protein (At3g62900) was identified as a putative signalling factor mediating gene regulation to reactive electrophilic oxylipin. We used microarrays to investigate the effect of a defect in the zinc finger on gene expression.

2025-02-20 | GSE286411 | GEO

Multiparameter functional diversity of human C2H2 zinc finger proteins

Project description:We have identified protein protein interactions of 118 C2H2 zinc finger proteins by AP-MS using GFP-tagged constructs in order to understand their role in transcription regulation.

2016-12-09 | PXD003431 | Pride

Comprehensive screens and a universal zinc finger model enable transcription factor reprogramming 2 factor reprogrammingComprehensive screens and a universal zinc finger model enable transcription factor reprogramming

Project description:Programmable regulation of gene expression promises to be a powerful therapeutic venue for diseases caused by the misexpression of genes, haploinsufficiencies, or gain of function mutations. While dCas9-effector domain fusions have been used to alter expression levels, their in vivo application is limited by size and immunogenicity. Conversely, the Cys2His2 Zinc Finger domain offers ideal characteristics for in vivo use. However, their intricate engagement with the DNA has made the design of Zinc Finger arrays challenging. We here describe the screening of 49 billion protein-DNA interactions and development of the first deep learning model that solves Zinc Finger design for any genomic target. We demonstrate the versatility of designed Zinc Fingers as nucleases and as activators or repressors by seamlessly reprogramming human transcription factors.

2022-11-01 | GSE215330 | GEO

Transposable elements drive the evolution of metazoan zinc finger genes

Project description:Cys2-His2 Zinc finger genes (ZNFs) form the largest family of transcription factors in metazoans. Zebrafish posess a subfamily characterized by the presence of a domain dubbed Fish N-terminal Zinc finger associated (FiNZ). FiNZ-ZNFs are expressed at the onset of zygotic genome activation in zebrafishh, and blocking FiNZ-ZNF translation using morpholinos during early zebrafish embryogenesis results in a broad de-repression of young, transcriptionally active TEs.

2023-04-10 | GSE229157 | GEO

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