MTG16 regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors
Rachel E. Brown, … , Sarah P. Short, Christopher S. Williams
Rachel E. Brown, … , Sarah P. Short, Christopher S. Williams
Published May 3, 2022
Citation Information: JCI Insight. 2022;7(10):e153045. https://doi.org/10.1172/jci.insight.153045.
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Research Article Cell biology Gastroenterology

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

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 (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.

Authors

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

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Figure 6

MTG16-mediated colonic epithelial regeneration is dependent on its repression of E protein transcription factor–mediated transcription.

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MTG16-mediated colonic epithelial regeneration is dependent on its repre...
(A) Schematic of the DSS injury-regeneration model. (B–D) Colitis severity in Mtg16T/T (T/T) versus WT mice evaluated using (B) weight loss, (C) colon length, and (D) histologic injury (scoring system described in Supplemental Table 2). Representative images at left. Scale bar = 200 μm. (E) Percentage of colon with histologic findings, estimated from the distal end, as a measure of proximal extent of disease. (B–E) Data are combined from 2 independent experiments (n = 15 WT, 16 Mtg16T/T). (F) EdU+ cells in injury-adjacent, regenerating crypts in colons from mice injected with EdU 1 hour prior to sacrifice on day 9 (n = 30–50 crypts from n = 5 mice). Dashed white line indicates ulcerated epithelium. Scale bar = 100 μm. (B–F) *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by (B) repeated measures 2-way ANOVA followed by Holm-Šidák multiple-comparison tests or (C–F) 2-tailed Mann-Whitney test. (G and H) GSEA of distal Mtg16T/T versus WT colon crypt isolates following DSS injury-regeneration (n = 3) (gene sets described in Supplemental Tables 3 and 4 and citations in the supplement). Tag %, the percentage of gene hits before (for positive ES) or after (for negative ES) the peak in the running ES, indicating the percentage of genes contributing to the ES. FDR q < 0.05 is considered significant.