MTG16 (CBFA2T3) regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors

Author:

Brown Rachel E.ORCID,Jacobse JustinORCID,Anant Shruti A.ORCID,Blunt Koral M.ORCID,Chen BobORCID,Vega Paige N.ORCID,Jones Chase T.ORCID,Pilat Jennifer M.ORCID,Revetta Frank,Gorby Aidan H.ORCID,Stengel Kristy R.ORCID,Choksi Yash A.ORCID,Palin KimmoORCID,Piazuelo M. BlancaORCID,Washington M. Kay,Lau Ken S.ORCID,Goettel Jeremy A.ORCID,Hiebert Scott W.ORCID,Short Sarah P.ORCID,Williams Christopher S.ORCID

Abstract

AbstractAberrant epithelial differentiation and regeneration contribute to colon pathologies including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). MTG16 (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 (DSS)-induced colitis. Transcriptomic analyses implicated increased E box-binding transcription factor (E protein) activity in MTG16-deficient colon crypts. Using a novel mouse model with a point mutation that disrupts MTG16:E protein complex formation (Mtg16P209T), we established 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 to unaffected controls. Finally, uncoupling MTG16:E protein interactions only partially phenocopied the enhanced tumorigenicity of Mtg16-/- 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.Graphical Abstract

Publisher

Cold Spring Harbor Laboratory

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