The main focus of my research is understanding how the
epithelium responds to injury and how normal injury response
processes are subverted in the development of malignancy. I am
using the Myeloid Translocation Gene family as the model for these
studies, in particular the role of myeloid translocation genes
(MTGs) in intestinal biology with emphasis on gut development, stem
cell function, and epithelial migration. MTGR1 (Myeloid
Translocation Gene, Related-1), MTG8 and MTG16 are members of a
gene family originally identified as targets of chromosomal
translocation in acute myeloid leukemia (AML). MTG family members
act as transcriptional repressors and interact with other
corepressors mSin3, N-CoR/SMRT and histone deacetylases (HDAC1-3).
Chromosomal translocations often target master regulatory genes
that affect growth, differentiation and apoptosis. These
translocations create fusion proteins (e.g. RUNX1/MTG8 is the
fusion protein generated by the t(8;21) translocation), that
repress RUNX1-regulated genes. In addition, these fusion proteins
associate with endogenous MTG family members and possibly
inactivate MTG functions. This would suggest that loss of MTG
factor action might predispose the cell to tumorigenesis.
Consistent with this hypothesis, MTG16 was identified as a putative
tumor suppressor in breast cancer.
The critical role of MTG family members in gut biology was first uncovered when mice were genetically engineered to remove Mtg8/Eto. A quarter of these mice show a deletion of the entire midgut leading to embryonic lethality. Similar studies by the Hiebert lab with Mtgr1-null mice indicated that MTGR1 was required for the formation of the secretory lineage in the small intestine. In unpublished work from the Hiebert lab, Mtg16-null animals display a dramatic hematopoetic stem cell defect (Irvin et al.,). Furthermore, the gut in these animals shows increased proliferation and slight increase in epithelial apoptosis. We have identified TCF4, the terminal effector of wnt signaling, as a binding partner for MTG mediated repression, thus implicating MTGs in negatively regulating wnt signals. To uncover further colonic phenotypes we stressed the stem cell compartment of the colon by inducing colitis using dextran sodium sulfate, an agent commonly used to induce acute colitis in rodents. We uncovered a striking phenotype, namely that these animals developed a severe, intense colitis; which translated into chronic colitis. Collectively, the gene knockout studies suggest that MTG transcriptional co-repressors play a critical role in stem-cell biology in both the gut and in hematopoiesis. I am currently investigating three important aspects of MTGs in intestinal biology
Mtgr1-null mice exhibit increased enterocyte proliferation, apoptosis, enhanced epithelial migration and exhibit a profound sensitivity to chemically induced colitis. My laboratory is focused on defining the molecular basis for these observations and to determine the relevance to inflammatory bowel disease and inflammatory carcinogenesis. There are three main projects:
1) Functional characterization of MTG colorectal cancer associated mutations
A) Biochemical and biological characterization
B) in vivo characterization using a "knockin" mouse model
2) Determining the role of MTGs in epithelial wound healing and repair processes
A) Cell culture based studies using Mtgr1-null conditionally transformed intestinal epithelial cell lines
B) Intestinal injury models using Mtgr1 and Mtg16-null mice.
C) Colorectal carcinogenesis models (AOM/DSS, Min mouse) intercrosses.
3) Role of co-repressor complex composition on function with emphasis on Kaiso-MTG interactions.
The following timeline graph is generated from all co-authored publications.Featured publications are shown below:
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MeSH terms are retrieved from PubMed records. Learn more.
Key: MeSH Term Keywordanimal models of wound healing Anticarcinogenic Agents Carcinoma Celecoxib colitis colon cancer Cyclooxygenase 2 Inhibitors Cyclooxygenase Inhibitors Endothelium, Vascular Enterocytes epithelial biology Gamma Rays Goblet Cells HT29 Cells Hypertension IBD Inflammation Interleukin-6 Interleukin-17 Kidney Lymphokines Mice, Transgenic Middle Aged Muscle Proteins Neoplasms, Experimental Oligonucleotide Probes Organ Size Polymorphism, Genetic Pulmonary Embolism Reverse Transcriptase Polymerase Chain Reaction Selenoprotein P Signal Transduction Tomography, X-Ray Computed Transcription, Genetic Transcription Factor 7-Like 2 Protein