MTG16 regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors

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Brown , R E , Jacobse , J , Anant , S A , Blunt , K M , Chen , B , Vega , P N , Jones , C T , Pilat , J M , Revetta , F , Gorby , A H , Stengel , K R , Choksi , Y A , Palin , K , Piazuelo , M B , Washington , M K , Lau , K S , Goettel , J A , Hiebert , S W , Short , S P & Williams , C S 2022 , ' MTG16 regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors ' , JCI INSIGHT , vol. 7 , no. 10 , 153045 . https://doi.org/10.1172/jci.insight.153045

Title: MTG16 regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors
Author: Brown, Rachel E.; Jacobse, Justin; Anant, Shruti A.; Blunt, Koral M.; Chen, Bob; Vega, Paige N.; Jones, Chase T.; Pilat, Jennifer M.; Revetta, Frank; Gorby, Aidan H.; Stengel, Kristy R.; Choksi, Yash A.; Palin, Kimmo; Piazuelo, M. Blanca; Washington, Mary Kay; Lau, Ken S.; Goettel, Jeremy A.; Hiebert, Scott W.; Short, Sarah P.; Williams, Christopher S.
Contributor organization: Lauri Antti Aaltonen / Principal Investigator
University of Helsinki
Department of Medical and Clinical Genetics
ATG - Applied Tumor Genomics
Digital Precision Cancer Medicine (iCAN)
Date: 2022-05-23
Language: eng
Number of pages: 22
Belongs to series: JCI INSIGHT
ISSN: 2379-3708
DOI: https://doi.org/10.1172/jci.insight.153045
URI: http://hdl.handle.net/10138/345970
Abstract: 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 with a point mutation that attenuates MTG16:E protein interactions (Mtg16(P20ST)), 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(-/)(-) colon in the azoxymethane/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.
Subject: GOBLET CELL-DIFFERENTIATION
ACUTE MYELOID-LEUKEMIA
ENTEROENDOCRINE CELLS
FUSION PARTNER
RETINOIC ACID
EXPRESSION
PROGENITOR
ATLAS
RNA
ENDOCRINE
3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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