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 In unpublished work from the Hiebert lab, Mtg16-null animals display a dramatic hematopoetic stem cell defect (Irvin et al.,).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. Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma. Short SP, Barrett CW, Stengel KR, Revetta FL, Choksi YA, Coburn LA, Lintel MK, McDonough EM, Washington MK, Wilson KT, Prokhortchouk E, Chen X, Hiebert SW, Reynolds AB, Williams CS (2019) Oncogene 38(25): 5091-5106
    › Primary publication · 30858547 (PubMed) · PMC6586520 (PubMed Central)
  2. Serum Polyunsaturated Fatty Acids Correlate with Serum Cytokines and Clinical Disease Activity in Crohn's Disease. Scoville EA, Allaman MM, Adams DW, Motley AK, Peyton SC, Ferguson SL, Horst SN, Williams CS, Beaulieu DB, Schwartz DA, Wilson KT, Coburn LA (2019) Sci Rep 9(1): 2882
    › Primary publication · 30814550 (PubMed) · PMC6393448 (PubMed Central)
  3. Blood vessel epicardial substance (BVES) reduces LRP6 receptor and cytoplasmic -catenin levels to modulate Wnt signaling and intestinal homeostasis. Thompson JJ, Short SP, Parang B, Brown RE, Li C, Ng VH, Saito-Diaz K, Choksi YA, Washington MK, Smith JJ, Fingleton B, Brand T, Lee E, Coffey RJ, Williams CS (2019) Carcinogenesis
    › Primary publication · 30689807 (PubMed)
  4. Serine Threonine Kinase 17A Maintains the Epithelial State in Colorectal Cancer Cells. Short SP, Thompson JJ, Bilotta AJ, Chen X, Revetta FL, Washington MK, Williams CS (2019) Mol Cancer Res 17(4): 882-894
    › Primary publication · 30655319 (PubMed)
  5. Is a Tumor Suppressor Gene in Colorectal Cancer. Chen MS, Lo YH, Chen X, Williams CS, Donnelly JM, Criss ZK, Patel S, Butkus JM, Dubrulle J, Finegold MJ, Shroyer NF (2019) Mol Cancer Res 17(3): 697-708
    › Primary publication · 30606770 (PubMed)
  6. Training the physician-scientist: views from program directors and aspiring young investigators. Williams CS, Iness AN, Baron RM, Ajijola OA, Hu PJ, Vyas JM, Baiocchi R, Adami AJ, Lever JM, Klein PS, Demer L, Madaio M, Geraci M, Brass LF, Blanchard M, Salata R, Zaidi M (2018) JCI Insight 3(23)
    › Primary publication · 30518696 (PubMed) · PMC6328016 (PubMed Central)
  7. Blood Vessel Epicardial Substance (BVES) in junctional signaling and cancer. Parang B, Thompson JJ, Williams CS (2018) Tissue Barriers 6(4): 1-12
    › Primary publication · 30307367 (PubMed) · PMC6389126 (PubMed Central)
  8. Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis. Coburn LA, Singh K, Asim M, Barry DP, Allaman MM, Al-Greene NT, Hardbower DM, Polosukhina D, Williams CS, Delgado AG, Piazuelo MB, Washington MK, Gobert AP, Wilson KT (2019) Oncogene 38(7): 1067-1079
    › Primary publication · 30202097 (PubMed) · PMC6377304 (PubMed Central)
  9. BVES is required for maintenance of colonic epithelial integrity in experimental colitis by modifying intestinal permeability. Choksi YA, Reddy VK, Singh K, Barrett CW, Short SP, Parang B, Keating CE, Thompson JJ, Verriere TG, Brown RE, Piazuelo MB, Bader DM, Washington MK, Mittal MK, Brand T, Gobert AP, Coburn LA, Wilson KT, Williams CS (2018) Mucosal Immunol 11(5): 1363-1374
    › Primary publication · 29907869 (PubMed) · PMC6162166 (PubMed Central)
  10. Roles for selenium and selenoprotein P in the development, progression, and prevention of intestinal disease. Short SP, Pilat JM, Williams CS (2018) Free Radic Biol Med : 26-35
    › Primary publication · 29778465 (PubMed) · PMC6168360 (PubMed Central)
  11. Alterations in Lipid, Amino Acid, and Energy Metabolism Distinguish Crohn's Disease from Ulcerative Colitis and Control Subjects by Serum Metabolomic Profiling. Scoville EA, Allaman MM, Brown CT, Motley AK, Horst SN, Williams CS, Koyama T, Zhao Z, Adams DW, Beaulieu DB, Schwartz DA, Wilson KT, Coburn LA (2018) Metabolomics 14(1): 17
    › Primary publication · 29681789 (PubMed) · PMC5907923 (PubMed Central)
  12. APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway. Saito-Diaz K, Benchabane H, Tiwari A, Tian A, Li B, Thompson JJ, Hyde AS, Sawyer LM, Jodoin JN, Santos E, Lee LA, Coffey RJ, Beauchamp RD, Williams CS, Kenworthy AK, Robbins DJ, Ahmed Y, Lee E (2018) Dev Cell 44(5): 566-581.e8
    › Primary publication · 29533772 (PubMed) · PMC5884143 (PubMed Central)
  13. Reovirus-Induced Apoptosis in the Intestine Limits Establishment of Enteric Infection. Brown JJ, Short SP, Stencel-Baerenwald J, Urbanek K, Pruijssers AJ, McAllister N, Ikizler M, Taylor G, Aravamudhan P, Khomandiak S, Jabri B, Williams CS, Dermody TS (2018) J Virol 92(10)
    › Primary publication · 29514905 (PubMed) · PMC5923068 (PubMed Central)
  14. Protein Phosphatase 2A in the Regulation of Wnt Signaling, Stem Cells, and Cancer. Thompson JJ, Williams CS (2018) Genes (Basel) 9(3)
    › Primary publication · 29495399 (PubMed) · PMC5867842 (PubMed Central)
  15. Best Practices for Physician-Scientist Training Programs: Recommendations from the Alliance for Academic Internal Medicine. Blanchard M, Burton MC, Geraci MW, Madaio MP, Marsh JD, Proweller A, Rockey DC, Salata RA, Tan W, Williams CS, Zaidi M, Todd RF (2018) Am J Med 131(5): 578-584
    › Primary publication · 29410155 (PubMed)
  16. Using 3D Organoid Cultures to Model Intestinal Physiology and Colorectal Cancer. Short SP, Costacurta PW, Williams CS (2017) Curr Colorectal Cancer Rep 13(3): 183-191
    › Primary publication · 29276469 (PubMed) · PMC5736147 (PubMed Central)
  17. Selenoproteins in Tumorigenesis and Cancer Progression. Short SP, Williams CS (2017) Adv Cancer Res : 49-83
    › Primary publication · 29054422 (PubMed) · PMC5819884 (PubMed Central)
  18. MTG16 is a tumor suppressor in colitis-associated carcinoma. McDonough EM, Barrett CW, Parang B, Mittal MK, Smith JJ, Bradley AM, Choksi YA, Coburn LA, Short SP, Thompson JJ, Zhang B, Poindexter SV, Fischer MA, Chen X, Li J, Revetta FL, Naik R, Washington MK, Rosen MJ, Hiebert SW, Wilson KT, Williams CS (2017) JCI Insight 2(16)
    › Primary publication · 28814670 (PubMed) · PMC5621889 (PubMed Central)
  19. BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis. Parang B, Kaz AM, Barrett CW, Short SP, Ning W, Keating CE, Mittal MK, Naik RD, Washington MK, Revetta FL, Smith JJ, Chen X, Wilson KT, Brand T, Bader DM, Tansey WP, Chen R, Brentnall TA, Grady WM, Williams CS (2017) Gut 66(5): 852-862
    › Primary publication · 28389570 (PubMed) · PMC5385850 (PubMed Central)
  20. Interleukin-22 drives nitric oxide-dependent DNA damage and dysplasia in a murine model of colitis-associated cancer. Wang C, Gong G, Sheh A, Muthupalani S, Bryant EM, Puglisi DA, Holcombe H, Conaway EA, Parry NAP, Bakthavatchalu V, Short SP, Williams CS, Wogan GN, Tannenbaum SR, Fox JG, Horwitz BH (2017) Mucosal Immunol 10(6): 1504-1517
    › Primary publication · 28198364 (PubMed) · PMC5557711 (PubMed Central)
  21. 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)
  22. 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)
  23. 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)
  24. 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)
  25. 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)
  26. 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)
  27. 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)
  28. 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)
  29. 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)
  30. 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)