Mtgr1 Is a Transcriptional Corepressor That Is Required for Maintenance of the Secretory Cell Lineage in the Small Intestine

Abstract

Two members of the MTG/ETO family of transcriptional corepressors, MTG8 and MTG16, are disrupted by chromosomal translocations in up to 15% of acute myeloid leukemia cases. The third family member, MTGR1, was identified as a factor that associates with the t(8;21) fusion protein RUNX1-MTG8. We demonstrate that Mtgr1 associates with mSin3A, N-CoR, and histone deacetylase 3 and that when tethered to DNA, Mtgr1 represses transcription, suggesting that Mtgr1 also acts as a transcriptional corepressor. To define the biological function of Mtgr1, we created Mtgr1-null mice. These mice are proportionally smaller than their littermates during embryogenesis and throughout their life span but otherwise develop normally. However, these mice display a progressive reduction in the secretory epithelial cell lineage in the small intestine. This is not due to the loss of small intestinal progenitor cells expressing Gfi1, which is required for the formation of goblet and Paneth cells, implying that loss of Mtgr1 impairs the maturation of secretory cells in the small intestine.

ACKNOWLEDGMENTS

We thank the members of the Hiebert lab for helpful discussions and encouragement and the Vanderbilt-Ingram Cancer Center (CA68485) and the Vanderbilt Digestive Diseases Research Center (5P30DK58404-03) for support and the use of shared resources, including DNA sequencing, transgenic/ES cell, immunohistochemistry, microarray, and histological analyses.

This work was supported by National Institutes of Health grants RO1-CA87549, RO1-CA64140, RO1-CA77274, and RO1-CA112005 (S.W.H.); the Mouse Models of Human Cancer Consortium and CA46413 (R.J.C.); and Leukemia and Lymphoma Society postdoctoral fellowship 5074-03 (B.J.I.) and training grants T32DK07673 (A.M.) and T32-CA09582 (A.C.M.).