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 4

MTG16 represses E protein–mediated transcription of Neurog3.

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MTG16 represses E protein–mediated transcription of Neurog3. (A) Venn di...
(A) Venn diagram of upregulated (Padj < 0.05) genes from bulk RNA-Seq of WT versus Mtg16–/– (orange) and WT versus Mtg16T/T (T/T) (purple) distal colonic crypt isolates (n = 3–4) and genes with TSSs nearest to MTG16 peaks in a ChIP-Seq data set generated by Baulies et al. (16) (green). Table 1 provides more information about the common upregulated genes. (B) MTG16 occupancy of an E box (5′-CATNNG)-rich region 5′ to Neurog3 in ChIP-Seq by Baulies et al. (16). Scale: 0–2. (C and D) Staining and quantification of Neurog3+ EE progenitor cells by RNAscope in (C) WT versus Mtg16–/– colon (n = 10 WT and 9 Mtg16–/–) and (D) WT versus Mtg16T/T colon (n = 5 WT and 4 Mtg16T/T). *P < 0.05, **P < 0.01 by 2-tailed Mann-Whitney test. Scale bars = 100 μm.