The Bardwell laboratory is interested in the mechanisms of transcriptional repression and how inappropriate transcriptional regulation leads to cancer and developmental disorders. There are two major ongoing projects in the laboratory. One project focuses on the transcriptional corepressor BCOR, a component of a variant Polycomb repressive complex 1 (PRC1) complex. BCOR mediates regulation by the BCL6 oncoprotein in lymphomas but in other cancers mutations of BCOR have been found in a variety of cancer suggesting it functions as on tumor suppressor gene. Germline mutation of BCOR in females causes the X-linked developmental disorder Oculofaciocardiodental syndrome, OFCD. The other project is a longtime collaboration with David Zarkower on DMRT1, a transcription factor that plays critical roles in suppressing testis cancer, lineage restriction, maintenance of sex determination and testis development. Both projects combine in vivo studies of mouse development and cancer with in vitro biochemical and mechanistic studies.
Béguelin W, Teater M, Gearhart MD, Calvo Fernández MT, Goldstein RL, Cárdenas MG, Hatzi K, Rosen M, Shen H, Corcoran CM, Hamline MY, Gascoyne RD, Levine RL, Abdel-Wahab O, Licht JD, Shaknovich R, Elemento O, Bardwell* VJ, Melnick* AM. (2016) EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis. Cancer Cell. 2016; 30(2):197-213. *co-corresponding authors
Murphy MW, Lee JK, Rojo S, Gearhart MD, Kurahashi K, Banerjee S, Loeuille GA, Bashamboo A, McElreavey K, Zarkower D, Aihara* H, Bardwell* VJ. (2015) An ancient protein-DNA interaction underlying metazoan sex determination. Nat Struct Mol Biol. 22(6):442-51. *co-corresponding authors
Yang JA, Tubo NJ, Gearhart MD, Bardwell VJ, Jenkins MK. (2015) Cutting Edge: Bcl6-Interacting Corepressor Contributes to Germinal Center T Follicular Helper Cell Formation and B Cell Helper Function. J Immunol. 2015 194(12):5604-8.
Lindeman RE, Gearhart MD, Minkina A, Krentz AD, Bardwell VJ, Zarkower D. (2015) Sexual cell-fate reprogramming in the ovary by DMRT1. Curr Biol. 25(6):764-71.
Minkina, A., Matson, C.K., Lindeman, R.E., Ghyselinck, N.B., Bardwell, V.J., Zarkower D. (2014) DMRT1 Protects Male Gonadal Cells from Retinoid-Dependent Sexual Transdifferentiation. Dev. Cell. 9;29(5):511-20.
Hatzi, K., Jiang, Y., Huang, C., Garrett-Bakelman, F., Gearhart, M. D., Giannopoulou, E. G., Zumbo, P., Kirouac, D., Bhaskara, S., Polo, J. M., Kormaksson, M., Mackerell, A. D., Jr., Xue, F., Mason, D. E., Hiebert, S. W. , Prive, G. G., Cerchietti, L., Bardwell, V. J., Elemento, O., Melnick, A. (2013) A hybrid mechanism of action for BCL6 in B-cells defined by formation of functionally distinct complexes at enhancers and promoters. Cell Reports, 4(3):578-88.
Matson, C.K., Murphy, M.W., Griswold, M.D., Yoshida, S., Bardwell, V.J., Zarkower, D. (2010) The mammalian doublesex homolog DMRT1 is a transcriptional gatekeeper that controls the mitosis versus meiosis decision in male germ cells Dev Cell. 19(4):612-24.
Matson, C.K., Murphy, M.W., Sarver, A.L., Griswold, M.D., Bardwell, V.J.*, Zarkower, D.* (2011) DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature 476(7358):101-4. *co-corresponding authors
Murphy, M.W., Sarver, A.L., Rice, D., Hatzi, K., Ye, K., Melnick, A., Heckert, L.L., Zarkower, D., Bardwell, V.J. (2010) Genome-wide analysis of DNA binding and transcriptional regulation by the mammalian Doublesex homolog DMRT1 in the juvenile testis. Proc Natl Acad Sci U S A. 27;107(30):13360-5.
Wamstad, J.A., Corcoran, C.M., Keating, A.M. and Bardwell, V.J. (2008) Role of the Transcriptional Corepressor Bcor in ES Cell Differentiation and Early Embryonic Development. PLoS ONE 30;3(7):e2814.
Hamline, M. Y., Corcoran, C. M., Miletich, I., Wamstad, J. A., Sharpe, P. T., and Bardwell, V. J., Oculofaciocardiodental (OFCD) Syndrome Craniofacial, Limb, and Cardiac Developmental Defects Are Revealed Upon Conditional Loss of the Polycomb-group Repressive Complex 1 (PRC1) Component BCOR (under revision for Developmental Biology)