Christopher Shawn Williams, M.D., Ph.D.
Assistant Professor of Medicine
Assistant Professor of Cancer Biology
Vanderbilt University Medical Center, Gastroenterology Division
1030-C Medical Research Building IV
Nashville, TN 37232-0252
Epigenetic control of intestinal epithelial wound healing and repair programs and relationship to colorectal oncogenesis.
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 In unpublished work from the Hiebert lab, Mtg16-null animals display a dramatic hematopoetic stem cell defect (Irvin et al.,).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.
- Coburn, LA, Gong, X, Singh, K, Asim, M, Scull, BP, Allaman, MM, Williams, CS, Rosen, MJ, Washington, MK, Barry, DP, Piazuelo, MB, Casero, RA, Chaturvedi, R, Zhao, Z, Wilson, KT L-arginine supplementation improves responses to injury and inflammation in dextran sulfate sodium colitis. PLoS One, 7(3), e33546, 2012.
- Williams, CS, Zhang, B, Smith, JJ, Jayagopal, A, Barrett, CW, Pino, C, Russ, P, Presley, SH, Peng, D, Rosenblatt, DO, Haselton, FR, Yang, JL, Washington, MK, Chen, X, Eschrich, S, Yeatman, TJ, El-Rifai, W, Beauchamp, RD, Chang, MS BVES regulates EMT in human corneal and colon cancer cells and is silenced via promoter methylation in human colorectal carcinoma. J Clin Invest, 121(10), 4056-69, 2011.
- Russ, PK, Pino, CJ, Williams, CS, Bader, DM, Haselton, FR, Chang, MS Bves modulates tight junction associated signaling. PLoS One, 6(1), e14563, 2011.
- Barrett, CW, Fingleton, B, Williams, A, Ning, W, Fischer, MA, Washington, MK, Chaturvedi, R, Wilson, KT, Hiebert, SW, Williams, CS MTGR1 is required for tumorigenesis in the murine AOM/DSS colitis-associated carcinoma model. Cancer Res, 71(4), 1302-12, 2011.
- Hong, SK, Chaturvedi, R, Piazuelo, MB, Coburn, LA, Williams, CS, Delgado, AG, Casero, RA, Schwartz, DA, Wilson, KT Increased expression and cellular localization of spermine oxidase in ulcerative colitis and relationship to disease activity. Inflamm Bowel Dis, 16(9), 1557-66, 2010.
- Whittem, CG, Williams, AD, Williams, CS Murine Colitis modeling using Dextran Sulfate Sodium (DSS). J Vis Exp, (35), 2010.
- Farmer, TE, Williams, CS, Washington, MK, Hiebert, SW Inactivation of the p19(ARF) tumor suppressor affects intestinal epithelial cell proliferation and integrity. J Cell Biochem, 104(6), 2228-40, 2008.
- Moore, AC, Amann, JM, Williams, CS, Tahinci, E, Farmer, TE, Martinez, JA, Yang, G, Luce, KS, Lee, E, Hiebert, SW Myeloid Translocation Gene Family Members Associate with TCFs and Influence TCF-Dependent Transcription. Mol Cell Biol, 2007.
- Martinez, JA, Williams, CS, Amann, JM, Ellis, TC, Moreno-Miralles, I, Washington, MK, Gregoli, P, Hiebert, SW Deletion of Mtgr1 sensitizes the colonic epithelium to dextran sodium sulfate-induced colitis. Gastroenterology, 131(2), 579-88, 2006.
- Smith, DS, Williams, CS, Ferris, CD Diagnosis and treatment of chronic gastroparesis and chronic intestinal pseudo-obstruction. Gastroenterol Clin North Am, 32(2), 619-58, 2003.
- Aklog, L, Williams, CS, Byrne, JG, Goldhaber, SZ Acute pulmonary embolectomy: a contemporary approach. Circulation, 105(12), 1416-9, 2002.
- Williams, CS, Sheng, H, Brockman, JA, Armandla, R, Shao, J, Washington, MK, Elkahloun, AG, DuBois, RN A cyclooxygenase-2 inhibitor (SC-58125) blocks growth of established human colon cancer xenografts. Neoplasia, 3(5), 428-36, 2001.
- Mann, M, Sheng, H, Shao, J, Williams, CS, Pisacane, PI, Sliwkowski, MX, DuBois, RN Targeting cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth. Gastroenterology, 120(7), 1713-9, 2001.
- Williams, CS, Watson, AJ, Sheng, H, Helou, R, Shao, J, DuBois, RN Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models. Cancer Res, 60(21), 6045-51, 2000.
- Williams, CS, Tsujii, M, Reese, J, Dey, SK, DuBois, RN Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest, 105(11), 1589-94, 2000.
- Callejas, NA, BoscÃ¡, L, Williams, CS, DuBOIS, RN, MartÃn-Sanz, P Regulation of cyclooxygenase 2 expression in hepatocytes by CCAAT/enhancer-binding proteins. Gastroenterology, 119(2), 493-501, 2000.
- Sheng, H, Shao, J, Dixon, DA, Williams, CS, Prescott, SM, DuBois, RN, Beauchamp, RD Transforming growth factor-beta1 enhances Ha-ras-induced expression of cyclooxygenase-2 in intestinal epithelial cells via stabilization of mRNA. J Biol Chem, 275(9), 6628-35, 2000.
- Williams, CS, Goldman, AP, Sheng, H, Morrow, JD, DuBois, RN Sulindac sulfide, but not sulindac sulfone, inhibits colorectal cancer growth. Neoplasia, 1(2), 170-6, 1999.
- Williams, CS, Shattuck-Brandt, RL, DuBois, RN The role of COX-2 in intestinal cancer. Expert Opin Investig Drugs, 8(1), 1-12, 1999.
- Williams, CS, Mann, M, DuBois, RN The role of cyclooxygenases in inflammation, cancer, and development. Oncogene, 18(55), 7908-16, 1999.
- Sheng, H, Williams, CS, Shao, J, Liang, P, DuBois, RN, Beauchamp, RD Induction of cyclooxygenase-2 by activated Ha-ras oncogene in Rat-1 fibroblasts and the role of mitogen-activated protein kinase pathway. J Biol Chem, 273(34), 22120-7, 1998.
- Goldman, AP, Williams, CS, Sheng, H, Lamps, LW, Williams, VP, Pairet, M, Morrow, JD, DuBois, RN Meloxicam inhibits the growth of colorectal cancer cells. Carcinogenesis, 19(12), 2195-9, 1998.
- Sheng, H, Shao, J, Williams, CS, Pereira, MA, Taketo, MM, Oshima, M, Reynolds, AB, Washington, MK, DuBois, RN, Beauchamp, RD Nuclear translocation of beta-catenin in hereditary and carcinogen-induced intestinal adenomas. Carcinogenesis, 19(4), 543-9, 1998.
- Inoue, I, Nakajima, T, Williams, CS, Quackenbush, J, Puryear, R, Powers, M, Cheng, T, Ludwig, EH, Sharma, AM, Hata, A, Jeunemaitre, X, Lalouel, JM A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro. J Clin Invest, 99(7), 1786-97, 1997.
- Williams, CS, Smalley, W, DuBois, RN Aspirin use and potential mechanisms for colorectal cancer prevention. J Clin Invest, 100(6), 1325-9, 1997.
- Zhang, T, Nanney, LB, Peeler, MO, Williams, CS, Lamps, L, Heppner, KJ, DuBois, RN, Beauchamp, RD Decreased transforming growth factor beta type II receptor expression in intestinal adenomas from Min/+ mice is associated with increased cyclin D1 and cyclin-dependent kinase 4 expression. Cancer Res, 57(9), 1638-43, 1997.
- Williams, CS, Luongo, C, Radhika, A, Zhang, T, Lamps, LW, Nanney, LB, Beauchamp, RD, DuBois, RN Elevated cyclooxygenase-2 levels in Min mouse adenomas. Gastroenterology, 111(4), 1134-40, 1996.
- DuBois, RN, Eberhart, CF, Williams, CS Introduction to eicosanoids and the gastroenteric tract. Gastroenterol Clin North Am, 25(2), 267-77, 1996.
- Hunt, SC, Williams, CS, Sharma, AM, Inoue, I, Williams, RR, Lalouel, JM Lack of linkage between the endothelial nitric oxide synthase gene and hypertension. J Hum Hypertens, 10(1), 27-30, 1996.
- Williams, CS, DuBois, RN Prostaglandin endoperoxide synthase: why two isoforms. Am J Physiol, 270(3 Pt 1), G393-400, 1996.
- Jeunemaitre, X, Soubrier, F, Kotelevtsev, YV, Lifton, RP, Williams, CS, Charru, A, Hunt, SC, Hopkins, PN, Williams, RR, Lalouel, JM Molecular basis of human hypertension: role of angiotensinogen. Cell, 71(1), 169-80, 1992.