MTG16 (CBFA2T3) regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract Aberrant epithelial differentiation and regeneration contribute to colon pathologies including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). MTG16 (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 (DSS)-induced colitis. Transcriptomic analyses implicated increased E box-binding transcription factor (E protein) activity in MTG16-deficient colon crypts. Using a novel mouse model with a point mutation that disrupts MTG16:E protein complex formation ( Mtg16 P209T ), we established 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 to unaffected controls. Finally, uncoupling MTG16:E protein interactions only partially phenocopied the enhanced tumorigenicity of Mtg16 -/- colon in the azoxymethane(AOM)/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. Graphical Abstract
Authors 20
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Affiliation as printed
Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA
Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA
Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, Tennessee, 373, USA
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Justin Jacobse Aachen
Vanderbilt University · Leiden University Medical Center · Willem-Alexander Kinderziekenhuis · Vanderbilt University Medical Center
Affiliation as printed
Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, USA
Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, The Netherlands
Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands
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Affiliation as printed
Vanderbilt University, Nashville, Tennessee, 37232, USA
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA
Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, 3232, USA
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA
Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Affiliation as printed
Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA
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Affiliation as printed
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, USA
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
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Vanderbilt University · VA Tennessee Valley Healthcare System · Vanderbilt University Medical Center
Affiliation as printed
Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA
Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee, 37232, USA
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Affiliation as printed
Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Affiliation as printed
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, USA
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Vanderbilt University · Vanderbilt-Ingram Cancer Center · Vanderbilt University Medical Center
Affiliation as printed
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA
Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, USA
Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA
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Vanderbilt University · Vanderbilt-Ingram Cancer Center · Vanderbilt University Medical Center
Affiliation as printed
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA
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Christopher S. Williams corresponding
Vanderbilt University · VA Tennessee Valley Healthcare System · Vanderbilt University Medical Center
Affiliation as printed
Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA
Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA
Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee, 37232, USA
Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, Tennessee, 373, USA
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