Manuel Diaz, MD
M.D., University of the Republic, School of Medicine Montevideo, Uruguay
Major Research Interests: Genetic Abnormalities Associated with Neoplasia
I am interested in understanding the role of fusion genes generated by chromosome translocations in human leukemia. MLL is a gene involved in such fusions, and the subject of research in my laboratory. We have focused on the role of conserved domains of MLL protein that are important in transcriptional activation of target genes, or alternatively in the repression of target genes. The protein Cyp33 that interacts with a conserved domain of MLL, can promote a switch in function of MLL from transcriptional activator to repressor. We have proposed that Cyp33, an RNA binding protein may be part of a mechanism that modulates the function of MLL in the presence of specific non-coding regulatory RNAs. Since the interaction between Cyp33 and MLL has a counterpart in the fruitfly Drosophila melanogaster, we are also performing comparative studies on the fly MLL protein homolog trithorax (trx), and its interaction with the fly Cyp33 protein. These studies involve transgenic flies, and are performed in collaboration with Dr. Andrew Dingwall. In this system, Cyp33 behaves as a polycomb-group gene.
Another question we are asking is how do the chromosome translocations that give rise to MLL-fusion genes arise, and we are exploring the hypothesis that they arise through defective repair of DNA breaks introduced by apoptotic enzymes in the middle of the MLL gene. In collaboration with Andrew Vaughan, we have been able to produce translocations and fusion genes in cells cultured in vitro and subjected to treatments that initiate the apoptotic process. A fraction of the cells that abort apoptosis and survive these treatments, give rise to progeny with translocations that fuse MLL to other genes. This gives us an in vitro system where we can explore the details of the breakage and repair mechanisms involved.
Guo Y, Niu C, Breslin P, Tang M, Zhang S, Wei W, Kini AR, Paner GP, Alkan S, Morris SW, Diaz M, Stiff PJ, Zhang. c-Myc-mediated control of cell fate in megakaryocyte-erythrocyte progenitors. J.Blood. 2009 Sep 3;114(10):2097-106. Epub 2009 Apr 16
Tie F, Banerjee R, Stratton CA, Prasad-Sinha J, Stepanik V, Zlobin A, Diaz MO, Scacheri PC, Harte PJ. CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila Polycomb silencing. Development. 136:3131-41, 2009
Le H, Singh S, Shih SJ, Du N, Schnyder S, Loredo GA, Bien C, Michaelis L, Toor A, Diaz MO, Vaughan AT. Rearrangements of the MLL gene are influenced by DNA secondary structure, potentially mediated by topoisomerase II binding. Genes Chromosomes Cancer. 48(9):806-15, 2009.
Erfurth, FE, Popovic, R, Grembecka, J, Cierpicki, T, Theisler, C, Xia, Z-B,Stuart, T., Diaz, MO, Bushweller, JH, Zeleznik-Le, NJ. MLL Protects CpG Clusters from Methylation within the Hoxa9 Gene, Maintaining Transcript Expression. Proc. Natl. Acad. Sci. USA, 105:7517-22, 2008.
Chen, J., Santillan, D., Koonce, M., Wei, W., Zeleznik-Le, N., Luo, R., Thirman, M., Diaz, M. O.. Loss of MLL PHD-fingers is necessary for MLL-ENL-induced hematopoietic stem cell immortalization. In press in Cancer Research, 2008.
Betti CJ, Villalobos MJ. Jiang Q, Cline E, Diaz MO, Loredo G, Vaughan ATM. Cleavage of the MLL gene by activators of apoptosis is independent of topoisomerase II activity. Leukemia 19:2289-95, 2005.
Xia, Z.B., Popovic, R., Chen, J., Theisler, C., Stuart, T., Santillan, D.A., Erfurth, F., Diaz, M.O., Zeleznik-Le, N.J.: The MLL fusion gene, MLL-AF4, regulates cyclin-dependent kinase inhibitor CDKN1B (p27kip1) expression. Proc Natl Acad Sci U S A. 102:14028-14033, (2005).
Betti, C.J., Villalobos, M.J., Jiang, Q., Cline, E., Diaz, M.O., Loredo, G., Vaughan, A.T.M.: Cleavage of the MLL gene by activators of apoptosis is independent of topoisomerase II activity. Leukemia. 19:2289-2295, (2005).
Xia Z, Anderson M, Diaz, M.O., Zeleznik-Le, N.J.: MLL repression domain activity is mediated by histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor CtBP.Proc. Natl. Acad. Sci. USA 100:8342-8347, (2003).