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The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation

Year: 2014
Type: article
Abstract: Notch signaling largely determines intestinal epithelial cell fate. High Notch activity drives progenitors toward absorptive enterocytes by repressing secretory differentiation programs, whereas low Notch permits secretory cell assignment. Myeloid translocation gene-related 1 (MTGR1) is a transcriptional corepressor in the myeloid translocation gene/Eight-Twenty-One family. Given that Mtgr1(-/-) mice have a dramatic reduction of intestinal epithelial secretory cells, we hypothesized that MTGR1 is a key repressor of Notch signaling. In support of this, transcriptome analysis of laser capture microdissected Mtgr1(-/-) intestinal crypts revealed Notch activation, and secretory markers Mucin2, Chromogranin A, and Growth factor-independent 1 (Gfi1) were down-regulated in Mtgr1(-/-) whole intestines and Mtgr1(-/-) enteroids. We demonstrate that MTGR1 is in a complex with Suppressor of Hairless Homolog, a key Notch effector, and represses Notch-induced Hairy/Enhancer of Split 1 activity. Moreover, pharmacologic Notch inhibition using a γ-secretase inhibitor (GSI) rescued the hyperproliferative baseline phenotype in the Mtgr1(-/-) intestine and increased production of goblet and enteroendocrine lineages in Mtgr1(-/-) mice. GSI increased Paneth cell production in wild-type mice but failed to do so in Mtgr1(-/-) mice. We determined that MTGR1 can interact with GFI1, a transcriptional corepressor required for Paneth cell differentiation, and repress GFI1 targets. Overall, the data suggest that MTGR1, a transcriptional corepressor well characterized in hematopoiesis, plays a critical role in intestinal lineage allocation.
DOI: 10.1096/fj.14-254284
Authors: Bobak Parang, Daniel Rosenblatt, Amanda D. Williams, Mary K. Washington, Frank Revetta, Sarah P. Short, Vishruth K. Reddy, Aubrey Hunt, Noah F. Shroyer, Michael E. Engel, Scott W. Hiebert, Christopher S. Williams
Institutions: Vanderbilt University, Lipscomb University, Baylor University, Baylor College of Medicine, University of Utah, Vanderbilt-Ingram Cancer Center, VA Tennessee Valley Healthcare System
Language: English
Open Access status: green
Funders: U.S. Department of Veterans Affairs, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
Awards: Regulation of MTG16 and Notch signaling in hematopoiesis, G1222447050, The role of MTGR1 in intestinal biology and inflammation, G191129599, G2736473211, G290007438, G2943695217, Medical Scientist Training Program, G4321410071, The Role of BVES in Intestinal Repair Programs and Inflammatory Bowel Disease, SPORE in GI Cancer, G4908180740, KLF5 regulation of intestinal development and stem cell homeostasis, G725763919, The Vanderbilt Institute for Clinical and Translational Research (VICTR), G9000083470, Molecular and Cellular Basis for Digestive Diseases
OpenAlex ID: W2123857063
FWCI: 0.544
Cites: 37
Cited by: 15
Related to: 10