JCI Insight (May 2022)

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

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

Journal volume & issue
Vol. 7, no. 10

Abstract

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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 (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–/– 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.

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