The work in my laboratory focuses on determining the normal function of the AML1/RUNX1 transcription factor in the regulation of hematopoietic gene expression and the mechanism by which the t(8;21), inv(16), and the t(12;21) chromosomal translocations disrupt normal AML-1 function to promote acute leukemia.  We have defined AML-1 as a transcription factor that binds the "enhancer core" motif, which regulates the expression of a large number of tissue specific genes. Transcriptional studies demonstrated that AML1 both activates and represses transcription, and that the translocation fusion proteins inhibit expression of AML1-dependent target genes.  We have determined that the t(8;21) fusion protein, AML1/ETO, interacts with the mSin3 and nuclear hormone co-repressors that recruit histone deacetylases to repress transcription.  This initial observation led us to demonstrate that the t(12;21) and inv(16) proteins also associate with co-repressors and histone deacetylases.  Thus, we have identified a common mechanism for transcriptional repression for these three translocations.  Given that these fusion proteins repress transcription and cause cancer, we asked whether they inhibit the expression of known tumor suppressor genes.  We have identified 2 tumor suppressors that are regulated by these translocation fusion proteins (p19ARF and Neurofibromatosis-1), which regulate the p53 tumor suppressor and the Ras oncogene, respectively.  We continue to use mouse models to dissect the molecular mechanisms by which these chromosomal translocation fusion proteins trigger acute leukemia.

In addition, we are examining the function of the ETO/MTG family of transcriptional co-repressors using gene ablation in the mouse.  Both ETO (also known as MTG8) and MTG16 (a closely related family member) are disrupted by chromosomal translocations in acute myeloid leukemia (the t(8;21) and t(16;21), respectively).  Moreover, MTG16 is commonly deleted in Breast cancer and ETO/MTG8 is mutated in colon cancer.  Disruption of ETO caused perinatal lethality with some defects in gut development and we are still exploring the cause(s) of death. Disruption of MTG16 caused defects in stem cell functions and disruptions in cell fate decisions.  Deletion of the third family member, Mtgr1, affected cell fate decisions in the small intestine.  Global gene expression analysis is being used to dissect the transcriptional changes upon deletion of these master regulators and to relate the inactivation phenotypes to tumorigenesis.  These studies have also linked the ETO family to the regulation of Wnt signaling and suggest that these factors function as tumor suppressors in Breast and Colon cancer.

Finally, we are extending our analysis of transcriptional control to the enzymes that are recruited by MTG family members and AML1/RUNX1.  Specifically, we have inactivated Histone Deacetylase 3 in the mouse. We are currently dissecting the phenotypes associated with inactivation of this key regulator of chromatin structure and function.  These phenotypes include cell cycle disruption, and wide spread changes in gene expression.

Publications

Featured publications

  1. Tgif1 regulates quiescence and self-renewal of hematopoietic stem cells. Yan L, Womack B, Wotton D, Guo Y, Shyr Y, Davé U, Li C, Hiebert S, Brandt S, Hamid R (2013) Mol Cell Biol 33(24): 4824-33
    › Primary publication · 24100014 (PubMed) · PMC3889555 (PubMed Central)
  2. HDAC3 is essential for DNA replication in hematopoietic progenitor cells. Summers AR, Fischer MA, Stengel KR, Zhao Y, Kaiser JF, Wells CE, Hunt A, Bhaskara S, Luzwick JW, Sampathi S, Chen X, Thompson MA, Cortez D, Hiebert SW (2013) J Clin Invest 123(7): 3112-23
    › Primary publication · 23921131 (PubMed) · PMC3696547 (PubMed Central)
  3. A hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters. Hatzi K, Jiang Y, Huang C, Garrett-Bakelman F, Gearhart MD, Giannopoulou EG, Zumbo P, Kirouac K, Bhaskara S, Polo JM, Kormaksson M, MacKerell AD, Xue F, Mason CE, Hiebert SW, Prive GG, Cerchietti L, Bardwell VJ, Elemento O, Melnick A (2013) Cell Rep 4(3): 578-88
    › Primary publication · 23911289 (PubMed) · PMC3854650 (PubMed Central)
  4. Inhibition of histone deacetylase 3 causes replication stress in cutaneous T cell lymphoma. Wells CE, Bhaskara S, Stengel KR, Zhao Y, Sirbu B, Chagot B, Cortez D, Khabele D, Chazin WJ, Cooper A, Jacques V, Rusche J, Eischen CM, McGirt LY, Hiebert SW (2013) PLoS One 8(7): e68915
    › Primary publication · 23894374 (PubMed) · PMC3718806 (PubMed Central)
  5. The transcriptional repressor NKAP is required for the development of iNKT cells. Thapa P, Das J, McWilliams D, Shapiro M, Sundsbak R, Nelson-Holte M, Tangen S, Anderson J, Desiderio S, Hiebert S, Sant'angelo DB, Shapiro VS (2013) Nat Commun : 1582
    › Primary publication · 23481390 (PubMed) · PMC3615467 (PubMed Central)
  6. Kaiso directs the transcriptional corepressor MTG16 to the Kaiso binding site in target promoters. Barrett CW, Smith JJ, Lu LC, Markham N, Stengel KR, Short SP, Zhang B, Hunt AA, Fingleton BM, Carnahan RH, Engel ME, Chen X, Beauchamp RD, Wilson KT, Hiebert SW, Reynolds AB, Williams CS (2012) PLoS One 7(12): e51205
    › Primary publication · 23251453 (PubMed) · PMC3521008 (PubMed Central)
  7. The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-κB. Ziesché E, Kettner-Buhrow D, Weber A, Wittwer T, Jurida L, Soelch J, Müller H, Newel D, Kronich P, Schneider H, Dittrich-Breiholz O, Bhaskara S, Hiebert SW, Hottiger MO, Li H, Burstein E, Schmitz ML, Kracht M (2013) Nucleic Acids Res 41(1): 90-109
    › Primary publication · 23087373 (PubMed) · PMC3592411 (PubMed Central)
  8. MTG16 contributes to colonic epithelial integrity in experimental colitis. Williams CS, Bradley AM, Chaturvedi R, Singh K, Piazuelo MB, Chen X, McDonough EM, Schwartz DA, Brown CT, Allaman MM, Coburn LA, Horst SN, Beaulieu DB, Choksi YA, Washington MK, Williams AD, Fisher MA, Zinkel SS, Peek RM, Wilson KT, Hiebert SW (2013) Gut 62(10): 1446-55
    › Primary publication · 22833394 (PubMed) · PMC3663894 (PubMed Central)
  9. Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages. Chen X, Barozzi I, Termanini A, Prosperini E, Recchiuti A, Dalli J, Mietton F, Matteoli G, Hiebert S, Natoli G (2012) Proc Natl Acad Sci U S A 109(42): E2865-74
    › Primary publication · 22802645 (PubMed) · PMC3479529 (PubMed Central)
  10. Myeloid translocation gene 16 is required for maintenance of haematopoietic stem cell quiescence. Fischer MA, Moreno-Miralles I, Hunt A, Chyla BJ, Hiebert SW (2012) EMBO J 31(6): 1494-505
    › Primary publication · 22266796 (PubMed) · PMC3321173 (PubMed Central)