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
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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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 2

MTG16 deficiency is associated with increased enteroendocrine cell markers, reserve stem cell gene signatures, and E protein target upregulation in the distal colon.

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MTG16 deficiency is associated with increased enteroendocrine cell marke...
(A) Unsupervised hierarchical clustering of differentially expressed genes in Mtg16–/– versus WT (n = 4) distal colonic epithelial isolates by RNA-Seq. Gene expression in individual samples is displayed by z score (normalized count). Genes of interest are labeled at right. (B) GSEA of distal colon RNA-Seq using gene sets representing epithelial cell types (described in Supplemental Tables 3 and 4 and cited in the supplement). Individual GSEA plots of EE and goblet cell signatures are displayed at right. (C) GSEA of distal colon RNA-Seq using gene sets representing stem and other progenitor cell populations (Supplemental Tables 3 and 4). (D) Staining and quantification of CHGA+ cells/crypt (top) stratified by location along the crypt axis (bottom). Scale bar = 50 μm. n = 10 WT, 9 Mtg16–/–. *P < 0.05, **P < 0.01 by 2-tailed Mann-Whitney test. TA, transit amplifying. (E) GSEA of distal colon RNA-Seq using MSigDB (51) gene sets representing E protein and Id protein transcriptional signatures (Supplemental Table 3). Individual GSEA plot of the E47 target gene signature at right. NES, normalized enrichment score (ES); 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.