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 3

MTG16-driven colonic epithelial lineage allocation is dependent on its repression of the E protein transcription factors E2A and HEB.

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MTG16-driven colonic epithelial lineage allocation is dependent on its r...
(A) WT and Mtg16T/T (T/T) mouse colon (n = 11 WT, 10 Mtg16T/T) stained for (A) goblet cells by PAS stain, (B) EE cells by immunofluorescence staining for CHGA, and (C) tuft cells by IHC for DCLK1. Representative images at left. Scale bars = 100 μm. *P < 0.05, **P < 0.01 by 2-tailed Mann-Whitney test. (D and E) Volcano plots demonstrating differentially expressed genes in (D) proximal (n = 2 WT, 2 Mtg16T/T) and (E) distal (n = 3 WT, 4 Mtg16T/T) colonic epithelial isolates by RNA-Seq. Horizontal dashed line indicates Padj < 0.05 by DESeq2. Vertical dashed lines indicate fold change = 1.5. Dot colors indicate goblet-associated (blue), EE-associated (red), and secretory-associated (black) genes. Dots outlined in orange represent genes that are upregulated or downregulated in the same direction in the corresponding Mtg16–/– colon segment (Dysreg. in 16–/–). (F–H) GSEA of distal colon RNA-Seq using gene sets representing (F and G) epithelial cell types and (H) E protein transcriptional signatures (Supplemental Tables 3 and 4). 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.