The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation

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

doi:10.1096/fj.14-254284

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The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation

Journal article

Open access

Peer reviewed

The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation

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, …

The FASEB journal, Vol.29(3), pp.786-795

03/2015

DOI: 10.1096/fj.14-254284

PMCID: PMC4763883

PMID: 25398765

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https://doi.org/10.1096/fj.14-254284View

Published (Version of record) Open Access

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.

Amyloid Precursor Protein Secretases - antagonists & inhibitors

Animals

Apoptosis - drug effects

Blotting, Western

Cell Differentiation - drug effects

Cell Lineage

Cell Proliferation - drug effects

Cells, Cultured

Epithelial Cells - cytology

Epithelial Cells - drug effects

Epithelial Cells - metabolism

Flow Cytometry

Immunoenzyme Techniques

Immunoprecipitation

Intestines - cytology

Intestines - drug effects

Intestines - metabolism

Mice

Mice, Knockout

Paneth Cells - cytology

Paneth Cells - drug effects

Paneth Cells - metabolism

Protease Inhibitors - pharmacology

Real-Time Polymerase Chain Reaction

Receptors, Notch - genetics

Receptors, Notch - metabolism

Repressor Proteins - physiology

Reverse Transcriptase Polymerase Chain Reaction

RNA, Messenger - genetics

Details

Title: Subtitle: The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation
Creators: Bobak Parang - University of Utah
Daniel Rosenblatt - Department of MedicineDivision of GastroenterologyVanderbilt UniversityNashvilleTennesseeUSA
Amanda D Williams
Mary K Washington - Vanderbilt University
Frank Revetta - Vanderbilt University
Sarah P Short - Department of MedicineDivision of GastroenterologyVanderbilt UniversityNashvilleTennesseeUSA
Vishruth K Reddy - Department of MedicineDivision of GastroenterologyVanderbilt UniversityNashvilleTennesseeUSA
Aubrey Hunt - Department of BiochemistryVanderbilt UniversityNashvilleTennesseeUSA
Noah F Shroyer - Division of Pediatrics-GastroenterologyBaylor University School of MedicineHoustonTexasUSA
Michael E Engel
Scott W Hiebert - Valley Health System
Christopher S Williams - University of Utah
Resource Type: Journal article
Publication Details: The FASEB journal, Vol.29(3), pp.786-795
DOI: 10.1096/fj.14-254284
PMID: 25398765
PMCID: PMC4763883
NLM abbreviation: FASEB J
ISSN: 0892-6638
eISSN: 1530-6860
Grant note: F30DK096718-01 / NIDDK NIH HHS P50 CA095103 / NCI NIH HHS R01 DK099204 / NIDDK NIH HHS P30 DK058404 / NIDDK NIH HHS K08 DK080221 / NIDDK NIH HHS R01DK092306 / NIDDK NIH HHS P30CA068485 / NCI NIH HHS R01 CA142826 / NCI NIH HHS T32 GM07347 / NIGMS NIH HHS K08DK080221 / NIDDK NIH HHS UL1 TR000445 / NCATS NIH HHS P30DK058404 / NIDDK NIH HHS I01 BX001426 / BLRD VA P30 CA068485 / NCI NIH HHS P50CA095103 / NCI NIH HHS K08 DK080190 / NIDDK NIH HHS R01CA178030 / NCI NIH HHS F30 DK096718 / NIDDK NIH HHS K08DK080190 / NIDDK NIH HHS R01 CA178030 / NCI NIH HHS T32 GM007347 / NIGMS NIH HHS UL1TR000445 / NCATS NIH HHS R01CA1428260 / NCI NIH HHS R01 DK092306 / NIDDK NIH HHS
Language: English
Date published: 03/2015
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984420940002771

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