Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma
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ABSTRACT:
PROVIDER: PRJNA512466 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8382990_1.fastq.gz | Fastqsanger.gz | |||
| SRR8382990_2.fastq.gz | Fastqsanger.gz | |||
| SRR8382991_1.fastq.gz | Fastqsanger.gz | |||
| SRR8382991_2.fastq.gz | Fastqsanger.gz | |||
| SRR8382982_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:The myeloid translocation gene family member MTG16 is a transcriptional corepressor that relies on the DNA-binding ability of other proteins to determine specificity. One such protein is the ZBTB family member Kaiso, and the MTG16:Kaiso interaction is necessary for repression of Kaiso target genes such as matrix metalloproteinase-7. Using the azoxymethane and dextran sodium sulfate (AOM/DSS) murine model of colitis-associated carcinoma, we previously determined that MTG16 loss accelerates tumorigenesis and inflammation. However, it was unknown whether this effect was modified by Kaiso-dependent transcriptional repression. To test for a genetic interaction between MTG16 and Kaiso in inflammatory carcinogenesis, we subjected single and double knockout (DKO) mice to the AOM/DSS protocol. Mtg16-/- mice demonstrated increased colitis and tumor burden; in contrast, disease severity in Kaiso-/- mice was equivalent to wild type controls. Surprisingly, Kaiso deficiency in the context of MTG16 loss reversed injury and pro-tumorigenic responses in the intestinal epithelium following AOM/DSS treatment, and tumor numbers were returned to near to wild type levels. Transcriptomic analysis of non-tumor colon tissue demonstrated that changes induced by MTG16 loss were widely mitigated by concurrent Kaiso loss, and DKO mice demonstrated downregulation of metabolism and cytokine-associated gene sets with concurrent activation of DNA damage checkpoint pathways as compared with Mtg16-/-. Further, Kaiso knockdown in intestinal enteroids reduced stem- and WNT-associated phenotypes, thus abrogating the induction of these pathways observed in Mtg16-/- samples. Together, these data suggest that Kaiso modifies MTG16-driven inflammation and tumorigenesis and suggests that Kaiso deregulation contributes to MTG16-dependent colitis and CAC phenotypes.
2019-04-02 | GSE124544 | GEO
Project description: Not available
| S-EPMC6586520 | biostudies-literature
Project description:Aberrant epithelial differentiation and regeneration contribute to colon pathologies, including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Myeloid translocation gene 16 (MTG16, also known as CBFA2T3) is a transcriptional corepressor expressed in the colonic epithelium. MTG16 deficiency in mice exacerbates colitis and increases tumor burden in CAC, though the underlying mechanisms remain unclear. Here, we identified MTG16 as a central mediator of epithelial differentiation, promoting goblet and restraining enteroendocrine cell development in homeostasis and enabling regeneration following dextran sulfate sodium–induced (DSS-induced) colitis. Transcriptomic analyses implicated increased Ephrussi box–binding transcription factor (E protein) activity in MTG16-deficient colon crypts. Using a mouse model homozygous for a point mutation that attenuates MTG16:E protein interactions (Mtg16P209T), we showed that MTG16 exerts control over colonic epithelial differentiation and regeneration by repressing E protein–mediated transcription. Mimicking murine colitis, MTG16 expression was increased in biopsies from patients with active IBD compared with unaffected controls. Finally, uncoupling MTG16:E protein interactions partially phenocopied the enhanced tumorigenicity of Mtg16-null colon in the azoxymethane (AOM) /DSS-induced model of CAC, indicating that MTG16 protects from tumorigenesis through additional mechanisms. Collectively, our results demonstrate that MTG16, via its repression of E protein targets, is a key regulator of cell fate decisions during colon homeostasis, colitis, and cancer.
2022-05-01 | GSE201768 | GEO
Project description:Kaiso (ZBTB33) is a transcription factor involved in mitotic clonal expansion and tumorigenesis in association with APC loss of heterozygosity. ENCODE data show strong overlap of the Kaiso promoter binding cite (eKBS) and many other transcription factors, including BRCA1. Here we sought to determine whether BRCA1 is a component of the Kaiso enhanceosome that regulates gene transcription. Using proximal ligation assays (PLA), immunoprecipitation followed by mass spectrometry, luciferase assays, and ChIP-seq experiments we evaluated the association between BRCA1 and Kaiso. Kaiso nuclear extract immunoprecipitation experiments revealed that Kaiso associates strongly with genes involved in RNA splicing and processing. When Kaiso was not cross linked to DNA, BRCA1 was not detected among Kaiso binding proteins. However, overexpression of BRCA1 increased Kaiso-mediated gene transcription in luciferase assays in a Kaiso-dependent manner. Comparison of BRCA1 ChIP-seq and Kaiso ChIP-seq data from HCT116 cells revealed both BRCA1 and Kaiso commonly bind to the promoters of 379 genes. The most enriched term associated with these genes where BRCA1 and Kaiso bind their promoters is metabolism of RNA. Disease processes associated with these BRCA1/Kaiso gene promoters indicate that BRCA1 is functionally linked to a Kaiso-directed program of RNAP2-mediated gene transcription and likely associated with colorectal cancer development and maintenance.
2025-06-16 | GSE294265 | GEO
Project description:Absence of the epigenetic regulator Kaiso suppresses Wnt driven intestinal tumourigenesis. To identify genes regulated by Kaiso we generated wild type and Kaiso-/- mice for microarray expression analysis to identify genes derepressed in the absence of Kaiso.
2018-12-05 | E-MTAB-6009 | biostudies-arrayexpress
Project description:The MTG family of transcriptional corepressors are frequent targets of chromosomal translocations and deletions in cancer, yet the mechanisms underlying tumor suppression are unclear. We employed a chemical-genetic approach to investigate the molecular mechanism of Mtg16-mediated repression. Analysis of nascent transcription revealed that Mtg16 is required to repress hundreds of genes and enhancers, including the oncogenes Myb and Gfi1b. Because Mtg16 tightly regulated its own transcription, this model yielded a rapid “on/off/on” switch for Mtg16, providing a unique opportunity to study maintenance and establishment of repression within the same system. Mtg16 directly opposed histone acetylation at regulated loci, but analysis of H3K27ac revealed that changes in this mark correlated better with Mtg16 itself than with transcriptional activity. Importantly, both the relationship between Mtg16 and Class I HDAC activity and Mtg16-mediated re-establishment of repression were dependent target transcription. We propose that Mtg16 acts as a transcription-sensitive damper at highly accessible loci.
2026-07-01 | GSE303354 | GEO
Project description:The MTG family of transcriptional corepressors are frequent targets of chromosomal translocations and deletions in cancer, yet the mechanisms underlying tumor suppression are unclear. We employed a chemical-genetic approach to investigate the molecular mechanism of Mtg16-mediated repression. Analysis of nascent transcription revealed that Mtg16 is required to repress hundreds of genes and enhancers, including the oncogenes Myb and Gfi1b. Because Mtg16 tightly regulated its own transcription, this model yielded a rapid “on/off/on” switch for Mtg16, providing a unique opportunity to study maintenance and establishment of repression within the same system. Mtg16 directly opposed histone acetylation at regulated loci, but analysis of H3K27ac revealed that changes in this mark correlated better with Mtg16 itself than with transcriptional activity. Importantly, both the relationship between Mtg16 and Class I HDAC activity and Mtg16-mediated re-establishment of repression were dependent target transcription. We propose that Mtg16 acts as a transcription-sensitive damper at highly accessible loci.
2026-07-01 | GSE303384 | GEO
Project description:Spermatogenesis is a highly coordinated process by which diploid spermatogonia (2n) differentiate into mature haploid (1n) spermatozoa in the seminiferous epithelium. Here, we show that Kaiso (Zbtb33) is critical to spermatogenesis, via binding to KBEs (Kaiso-binding elements) in the 5’ upstream regulatory regions of Gdnf and Plzf to repress their expression, promoting the differentiation of spermatogonial stem cells (SSCs). In Kaiso-/Y mice, Plzf and Gdnf were derepressed in both SSCs and Sertoli cells, explaining the increased number of SSCs observed in these abnormal mice. We also found that Bcl6, an antiapoptotic spermatocyte survival factor, represses the Crem pathway genes. In particular, Kaiso represses Bcl6 by binding two KBEs in the Bcl6 5’ upstream regulatory region and first intron, thus indirectly derepressing Crem and Crem pathway genes. In Kaiso-/Y mice, Bcl6 is overexpressed, and these mice lack differentiated post-mitotic cells and consequently, are infertile. Interestingly, epigenetic “marks,” histone post-translational modifications such as lysine methylation, within histone H3 (H3K27me3), of the promoters of Kaiso target genes, were found transgenerationally heritable, prior to “wash out” during generations 1-3 in Kaiso-/Y mice, thus impacting Kaiso target gene expression. Consequently, Kaiso, by repressing Plzf, Gdnf, and Bcl6, indirectly upregulates Crem, and thereby plays a critical role not only in SSC differentiation, but also in post-meiotic events during spermatogenesis.
2021-03-05 | GSE111409 | GEO
Project description: Not available
| S-EPMC3521008 | biostudies-literature
Project description: Not available
| S-EPMC5621889 | biostudies-literature