Profile

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 In unpublished work from the Hiebert lab, Mtg16-null animals display a dramatic hematopoetic stem cell defect (Irvin et al.,).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.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. BVES Regulates Intestinal Stem Cell Programs and Intestinal Crypt Viability after Radiation. Reddy VK, Short SP, Barrett CW, Mittal MK, Keating CE, Thompson JJ, Harris EI, Revetta F, Bader DM, Brand T, Washington MK, Williams CS (2016) Stem Cells 34(6): 1626-36
    › Primary publication · 26891025 (PubMed) · PMC4893006 (PubMed Central)
  2. Competition between the Brain and Testes under Selenium-Compromised Conditions: Insight into Sex Differences in Selenium Metabolism and Risk of Neurodevelopmental Disease. Pitts MW, Kremer PM, Hashimoto AC, Torres DJ, Byrns CN, Williams CS, Berry MJ (2015) J Neurosci 35(46): 15326-38
    › Primary publication · 26586820 (PubMed) · PMC4649005 (PubMed Central)
  3. Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage. Barrett CW, Reddy VK, Short SP, Motley AK, Lintel MK, Bradley AM, Freeman T, Vallance J, Ning W, Parang B, Poindexter SV, Fingleton B, Chen X, Washington MK, Wilson KT, Shroyer NF, Hill KE, Burk RF, Williams CS (2015) J Clin Invest 125(7): 2646-60
    › Primary publication · 26053663 (PubMed) · PMC4563672 (PubMed Central)
  4. ERBB4 is over-expressed in human colon cancer and enhances cellular transformation. Williams CS, Bernard JK, Demory Beckler M, Almohazey D, Washington MK, Smith JJ, Frey MR (2015) Carcinogenesis 36(7): 710-8
    › Primary publication · 25916654 (PubMed) · PMC4572918 (PubMed Central)
  5. Transcriptional corepressor MTG16 regulates small intestinal crypt proliferation and crypt regeneration after radiation-induced injury. Poindexter SV, Reddy VK, Mittal MK, Williams AM, Washington MK, Harris E, Mah A, Hiebert SW, Singh K, Chaturvedi R, Wilson KT, Lund PK, Williams CS (2015) Am J Physiol Gastrointest Liver Physiol 308(6): G562-71
    › Primary publication · 25573176 (PubMed) · PMC4360050 (PubMed Central)
  6. The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation. Parang B, Rosenblatt D, Williams AD, Washington MK, Revetta F, Short SP, Reddy VK, Hunt A, Shroyer NF, Engel ME, Hiebert SW, Williams CS (2015) FASEB J 29(3): 786-95
    › Primary publication · 25398765 (PubMed) · PMC4763883 (PubMed Central)
  7. High-throughput multi-analyte Luminex profiling implicates eotaxin-1 in ulcerative colitis. Coburn LA, Horst SN, Chaturvedi R, Brown CT, Allaman MM, Scull BP, Singh K, Piazuelo MB, Chitnavis MV, Hodges ME, Rosen MJ, Williams CS, Slaughter JC, Beaulieu DB, Schwartz DA, Wilson KT (2013) PLoS One 8(12): e82300
    › Primary publication · 24367513 (PubMed) · PMC3867379 (PubMed Central)
  8. The role of COX-2 in intestinal cancer. Williams C, Shattuck-Brandt RL, DuBois RN (1999) Ann N Y Acad Sci : 72-83
    › Primary publication · 10668484 (PubMed)
  9. Haplotypes of angiotensinogen in essential hypertension. Jeunemaitre X, Inoue I, Williams C, Charru A, Tichet J, Powers M, Sharma AM, Gimenez-Roqueplo AP, Hata A, Corvol P, Lalouel JM (1997) Am J Hum Genet 60(6): 1448-60
    › Primary publication · 9199566 (PubMed) · PMC1716122 (PubMed Central)
  10. Blunted renal vascular response to angiotensin II is associated with a common variant of the angiotensinogen gene and obesity. Hopkins PN, Lifton RP, Hollenberg NK, Jeunemaitre X, Hallouin MC, Skuppin J, Williams CS, Dluhy RG, Lalouel JM, Williams RR, Williams GH (1996) J Hypertens 14(2): 199-207
    › Primary publication · 8728297 (PubMed)