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| Status |
Public on Apr 02, 2019 |
| Title |
Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Adjacent normal colon tissue was harvested from WT, Kaiso-/-, Mtgt16-/-, and double knockout mice after conclusion of the AOM/DSS treatment protocol. 3 samples were used per genotype
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| Contributor(s) |
Short SP, Williams CS |
| Citation(s) |
30858547 |
| |
| Submission date |
Jan 02, 2019 |
| Last update date |
Apr 02, 2019 |
| Contact name |
Christopher Williams |
| E-mail(s) |
christopher.s.williams@vumc.org
|
| Phone |
6153220320
|
| Organization name |
Vanderbilt University Medical Center
|
| Street address |
2215-B Garland Ave, 1075 MRB4
|
| City |
Nashville |
| State/province |
Tennessee |
| ZIP/Postal code |
37232 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA512466 |
| SRA |
SRP174997 |
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