MTG16 is a tumor suppressor in colitis-associated carcinoma

Em, McDonough; Cw, Barrett; Parang, Bobak; Mk, Mittal; Jj, Smith; Am, Bradley; Ya, Choksi; Coburn, Lori A.; Short, Sarah P.; Jj, Thompson; Zhang, B; Sv, Poindexter; Ma, Fischer; Chen, X; Li, Jian; Fl, Revetta; Naik, Rishi D.; Mk, Washington; Rosen, Michael J.; Hiebert, SW; Kt, Wilson; Williams, Christopher S.

doi:10.1172/jci.insight.78210

Cited by 7 publications

(25 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We previously identified significantly higher numbers of tumors with high-grade dysplasia in AOM/DSS treated Mtg16 −/− mice, and this was again observed (WT: 0 out of 20 tumors, Mtg16 −/− : 5 out of 25 tumors, P <0.05, Fisher’s exact test, Fig. 4C & 4D) (21). Interestingly, a similarly high proportion of tumors with high-grade dysplasia were seen in the DKO cohort (4 out of 16 tumors, P <0.01 vs. WT, Fisher’s exact test).…”

Section: Resultsmentioning

confidence: 54%

“…Previously, we have observed MTG16 downregulation in tumors from the AOM/DSS CAC model, yet Kaiso expression in this model has not yet been reported (21). Therefore, we next assessed Kaiso ( Zbtb33 ) and MTG16 ( Cbfa2t3 ) expression to determine if the trends observed in sporadic CRC were maintained in inflammatory tumorigenesis.…”

Section: Resultsmentioning

confidence: 89%

“…We have recently determined that Mtg16 −/− mice demonstrate increased mucosal injury in response to the AOM/DSS protocol, resulting in increased weight loss, stool scores, and morbidity (21). We next aimed to determine whether these phenotypes were dependent on Kaiso expression and whether the inverse MTG16:Kaiso gene expression was relevant to inflammatory tumor formation (12).…”

Section: Resultsmentioning

confidence: 99%

“…We have previously determined Mtg16 −/− intestinal epithelium displays altered proliferation, apoptosis, and secretory lineage allocation at baseline and in the setting of AOM/DSS (21, 23, 24). As these phenotypes likely contribute to the augmented injury response observed in Mtg16 −/− AOM/DSS-treated mice, we next analyzed the effect of concurrent MTG16;Kaiso loss in colonic tissue at the conclusion of the AOM/DSS protocol (Fig.…”

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma

et al. 2019

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 54%

Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…has reported SNVs across all three MTG family members in multiple tumor types. The lack of an apparent mutational hotspot suggests that MTG family members may function as tumor suppressors, and this hypothesis is borne out in mouse models in which the loss of either Mtgr1 or Mtg16 triggered intestinal tumor formation in both APC min -driven and inflammatory-induced tumor models (Barrett et al, 2011;McDonough et al, 2017;Parang et al, 2016;Parang et al, 2015;Poindexter et al, 2015;Williams et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Mtg16-dependent repression of E protein activity is required for early lymphopoiesis

Acharya

Sampathi

Flaherty

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

The ETO/MTG family of transcriptional co-repressors play a key role in adult stem cell functions in various tissues. These factors are commonly found in complex with E proteins such as E2A, HEB, and Lyl1 as well as PRDM14 and BTB/POZ domain factors. Structural studies identified a region in the first domain of MTGs that is conserved in the Drosophila homologue Nervy (Nervy Homology Domain-1, or NHR1) that is essential for ETO/MTG8 to inhibit E protein-dependent transcription. The Cancer Genome Atlas (TCGA) identified cancer associated single nucleotide variants (SNVs) near the MTG16:E protein contact site. We tested these SNVs using sensitive yeast two-hybrid association assays, which suggested that only P209T significantly affected E protein binding. We then used CRISPR-Cas9 and homology directed DNA repair to insert P209T and a known inactivating mutation, F210A, into NHR1 of Mtg16 in the germ line of mice. These mice developed normally, but in competitive bone marrow transplantation assays, the F210A-containing stem cells failed to contribute to lymphopoiesis, while P209T mutant cells were reduced in mature T cell populations. High content fluorescent activated analytical flow cytometry assays identified a defect in the multi-potent progenitor to common lymphoid progenitor transition during lymphopoiesis. These data indicate that the cancer associated changes are likely benign polymorphisms, and the MTG:E protein association is required for lymphopoiesis, but less important for myelopoiesis and stem cell functions.

show abstract

MTGR1 is required to maintain small intestinal stem cell populations

Short,

Brown,

Chen

et al. 2024

Cell Death Differ

View full text Add to dashboard Cite

Undifferentiated intestinal stem cells (ISCs) are crucial for maintaining homeostasis and resolving injury. Lgr5+ cells in the crypt base constantly divide, pushing daughter cells upward along the crypt axis where they differentiate into specialized cell types. Coordinated execution of complex transcriptional programs is necessary to allow for the maintenance of undifferentiated stem cells while permitting differentiation of the wide array of intestinal cells necessary for homeostasis. Previously, members of the myeloid translocation gene (MTG) family have been identified as transcriptional co-repressors that regulate stem cell maintenance and differentiation programs in multiple organ systems, including the intestine. One MTG family member, myeloid translocation gene related 1 (MTGR1), has been recognized as a crucial regulator of secretory cell differentiation and response to injury. However, whether MTGR1 contributes to the function of ISCs has not yet been examined. Here, using Mtgr1−/− mice, we have assessed the effects of MTGR1 loss specifically in ISC biology. Interestingly, loss of MTGR1 increased the total number of cells expressing Lgr5, the canonical marker of cycling ISCs, suggesting higher overall stem cell numbers. However, expanded transcriptomic and functional analyses revealed deficiencies in Mtgr1-null ISCs, including deregulated ISC-associated transcriptional programs. Ex vivo, intestinal organoids established from Mtgr1-null mice were unable to survive and expand due to aberrant differentiation and loss of stem and proliferative cells. Together, these results indicate that the role of MTGR1 in intestinal differentiation is likely stem cell intrinsic and identify a novel role for MTGR1 in maintaining ISC function.

show abstract

MTG16 is a tumor suppressor in colitis-associated carcinoma

Cited by 7 publications

References 47 publications

Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma

Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma

Mtg16-dependent repression of E protein activity is required for early lymphopoiesis

MTGR1 is required to maintain small intestinal stem cell populations

Contact Info

Product

Resources

About