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bioRxiv · 10.1101/2021.11.03.467178

MTG16 (CBFA2T3) represses E protein-dependent transcription to regulate colonic secretory cell differentiation, epithelial regeneration, and tumorigenesis

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.
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Abstract

Aberrant 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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/467178v3_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@21948borg.highwire.dtl.DTLVardef@9f60eeorg.highwire.dtl.DTLVardef@194b9fdorg.highwire.dtl.DTLVardef@13eb1a7_HPS_FORMAT_FIGEXP M_FIG C_FIG

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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.. 2021-11-04. MTG16 (CBFA2T3) represses E protein-dependent transcription to regulate colonic secretory cell differentiation, epithelial regeneration, and tumorigenesis. https://doi.org/10.1101/2021.11.03.467178

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