The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation.
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.
*Department of Medicine, Division of Gastroenterology, Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Biochemistry, Vanderbilt University, Nashville, Tennessee, USA; Department of Biology, Lipscomb University, Nashville, Tennessee, USA; Division of Pediatrics-Gastroenterology, Baylor University School of Medicine, Houston, Texas, USA; Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, Utah; and **Vanderbilt Ingram Cancer Center, Veterans Affairs, Tennessee Valley Health Care System, Nashville, Tennessee, USA.
Bobak
B
Parang
*Department of Medicine, Division of Gastroenterology, Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Biochemistry, Vanderbilt University, Nashville, Tennessee, USA; Department of Biology, Lipscomb University, Nashville, Tennessee, USA; Division of Pediatrics-Gastroenterology, Baylor University School of Medicine, Houston, Texas, USA; Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, Utah; and **Vanderbilt Ingram Cancer Center, Veterans Affairs, Tennessee Valley Health Care System, Nashville, Tennessee, USA.
Daniel
D
Rosenblatt
*Department of Medicine, Division of Gastroenterology, Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Biochemistry, Vanderbilt University, Nashville, Tennessee, USA; Department of Biology, Lipscomb University, Nashville, Tennessee, USA; Division of Pediatrics-Gastroenterology, Baylor University School of Medicine, Houston, Texas, USA; Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, Utah; and **Vanderbilt Ingram Cancer Center, Veterans Affairs, Tennessee Valley Health Care System, Nashville, Tennessee, USA.
Amanda D
AD
Williams
*Department of Medicine, Division of Gastroenterology, Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Biochemistry, Vanderbilt University, Nashville, Tennessee, USA; Department of Biology, Lipscomb University, Nashville, Tennessee, USA; Division of Pediatrics-Gastroenterology, Baylor University School of Medicine, Houston, Texas, USA; Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, Utah; and **Vanderbilt Ingram Cancer Center, Veterans Affairs, Tennessee Valley Health Care System, Nashville, Tennessee, USA.
Mary K
MK
Washington
*Department of Medicine, Division of Gastroenterology, Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Biochemistry, Vanderbilt University, Nashville, Tennessee, USA; Department of Biology, Lipscomb University, Nashville, Tennessee, USA; Division of Pediatrics-Gastroenterology, Baylor University School of Medicine, Houston, Texas, USA; Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, Utah; and **Vanderbilt Ingram Cancer Center, Veterans Affairs, Tennessee Valley Health Care System, Nashville, Tennessee, USA.
Frank
F
Revetta
*Department of Medicine, Division of Gastroenterology, Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Biochemistry, Vanderbilt University, Nashville, Tennessee, USA; Department of Biology, Lipscomb University, Nashville, Tennessee, USA; Division of Pediatrics-Gastroenterology, Baylor University School of Medicine, Houston, Texas, USA; Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, Utah; and **Vanderbilt Ingram Cancer Center, Veterans Affairs, Tennessee Valley Health Care System, Nashville, Tennessee, USA.
Sarah P
SP
Short
*Department of Medicine, Division of Gastroenterology, Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Biochemistry, Vanderbilt University, Nashville, Tennessee, USA; Department of Biology, Lipscomb University, Nashville, Tennessee, USA; Division of Pediatrics-Gastroenterology, Baylor University School of Medicine, Houston, Texas, USA; Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, Utah; and **Vanderbilt Ingram Cancer Center, Veterans Affairs, Tennessee Valley Health Care System, Nashville, Tennessee, USA.
Vishruth K
VK
Reddy
*Department of Medicine, Division of Gastroenterology, Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Biochemistry, Vanderbilt University, Nashville, Tennessee, USA; Department of Biology, Lipscomb University, Nashville, Tennessee, USA; Division of Pediatrics-Gastroenterology, Baylor University School of Medicine, Houston, Texas, USA; Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, Utah; and **Vanderbilt Ingram Cancer Center, Veterans Affairs, Tennessee Valley Health Care System, Nashville, Tennessee, USA.
Aubrey
A
Hunt
*Department of Medicine, Division of Gastroenterology, Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Biochemistry, Vanderbilt University, Nashville, Tennessee, USA; Department of Biology, Lipscomb University, Nashville, Tennessee, USA; Division of Pediatrics-Gastroenterology, Baylor University School of Medicine, Houston, Texas, USA; Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, Utah; and **Vanderbilt Ingram Cancer Center, Veterans Affairs, Tennessee Valley Health Care System, Nashville, Tennessee, USA.
Noah F
NF
Shroyer
*Department of Medicine, Division of Gastroenterology, Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Biochemistry, Vanderbilt University, Nashville, Tennessee, USA; Department of Biology, Lipscomb University, Nashville, Tennessee, USA; Division of Pediatrics-Gastroenterology, Baylor University School of Medicine, Houston, Texas, USA; Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, Utah; and **Vanderbilt Ingram Cancer Center, Veterans Affairs, Tennessee Valley Health Care System, Nashville, Tennessee, USA.
Michael E
ME
Engel
*Department of Medicine, Division of Gastroenterology, Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Biochemistry, Vanderbilt University, Nashville, Tennessee, USA; Department of Biology, Lipscomb University, Nashville, Tennessee, USA; Division of Pediatrics-Gastroenterology, Baylor University School of Medicine, Houston, Texas, USA; Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, Utah; and **Vanderbilt Ingram Cancer Center, Veterans Affairs, Tennessee Valley Health Care System, Nashville, Tennessee, USA.
Scott W
SW
Hiebert
*Department of Medicine, Division of Gastroenterology, Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Biochemistry, Vanderbilt University, Nashville, Tennessee, USA; Department of Biology, Lipscomb University, Nashville, Tennessee, USA; Division of Pediatrics-Gastroenterology, Baylor University School of Medicine, Houston, Texas, USA; Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, Utah; and **Vanderbilt Ingram Cancer Center, Veterans Affairs, Tennessee Valley Health Care System, Nashville, Tennessee, USA christopher.williams@vanderbilt.edu.
Christopher S
CS
Williams
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D019879:Paneth Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C110408:CBFA2T2 myeloid-transforming gene-related protein; D011480:Protease Inhibitors; D012333:RNA, Messenger; D051880:Receptors, Notch; D012097:Repressor Proteins; D053829:Amyloid Precursor Protein Secretases
CBFA2T2; Notch signaling; Paneth cells