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

doi:10.1172/jci.insight.153045

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

Journal article

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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, …

JCI insight, Vol.7(10), e153045

05/23/2022

DOI: 10.1172/jci.insight.153045

PMCID: PMC9220854

PMID: 35503250

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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.

Animals

Carcinogenesis - genetics

Carcinogenesis - metabolism

Cell Transformation, Neoplastic - genetics

Colitis - chemically induced

Colitis - genetics

Colitis - metabolism

Dextran Sulfate - toxicity

Humans

Inflammatory Bowel Diseases - genetics

Mice

Mice, Inbred C57BL

Mice, Knockout

Transcription Factors - genetics

Details

Title: Subtitle: MTG16 regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors
Creators: Rachel E Brown - Vanderbilt University
Justin Jacobse - Leiden University Medical Center
Shruti A Anant - Vanderbilt Health
Koral M Blunt - Vanderbilt University Medical Center
Bob Chen - Vanderbilt University
Paige N Vega - Vanderbilt University
Chase T Jones - Vanderbilt University Medical Center
Jennifer M Pilat - Vanderbilt University
Frank Revetta - Vanderbilt University
Aidan H Gorby - Vanderbilt University Medical Center
Kristy R Stengel - Vanderbilt University
Yash A Choksi - Vanderbilt University Medical Center
Kimmo Palin - University of Helsinki
M Blanca Piazuelo - Vanderbilt University Medical Center
Mary Kay Washington - Vanderbilt University
Ken S Lau - Vanderbilt University
Jeremy A Goettel - Vanderbilt University Medical Center
Scott W Hiebert - Vanderbilt University
Sarah P Short - Vanderbilt University Medical Center
Christopher S Williams - Vanderbilt University Medical Center
Resource Type: Journal article
Publication Details: JCI insight, Vol.7(10), e153045
DOI: 10.1172/jci.insight.153045
PMID: 35503250
PMCID: PMC9220854
NLM abbreviation: JCI Insight
ISSN: 2379-3708
eISSN: 2379-3708
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: F30DK120149, F31DK127687, F31CA232272, R01DK103831, U01CA215798, R03DK123489, R01CA178030, K01DK123495, F32DK108492, R01DK099204, P30DK058404, P50CA236733, P30CA068485, U24DK059637, T32GM00734; DOI: 10.13039/100000738, name: U.S. Department of Veterans Affairs, award: 1I01BX001426, IK2BX004648; DOI: 10.13039/100011684, name: Crohn’s and Colitis Foundation, award: 623541, 662877; DOI: 10.13039/501100001722, name: Royal Netherlands Academy of Arts and Sciences, award: Academy Ter Meulen Grant; name: Prince Bernhard Cultural Foundation, award: Cultural Foundation Grant; DOI: 10.13039/501100002341, name: Academy of Finland, award: 312041; name: iCAN Digital Precision Cancer Medicine Flagship, award: 320185; DOI: 10.13039/501100006306, name: Sigrid Jusélius Foundation, award: N/A
Language: English
Date published: 05/23/2022
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984420936502771

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