Mammalian gene regulation, Transcriptional modulation of the immune system
The research in my lab is focused on the molecular mechanisms that govern transcriptional regulation of genes in general, and during myeloid cell differentiation in particular. Bone marrow derived hematopoietic stem cells give rise to all blood cell types. This hierarchical cell fate decisions process is orchestrated by key transcription factors. These factors govern and modulate the expression of lineage specific genes. Lineage specific expression is the hallmark of this complex differentiation process, yet the molecular mechanisms that govern this lineage restricted expression are not elucidated. Interferon Regulatory Factor-8 (IRF-8) is a nuclear transcription factor that serves as a key factor in the hierarchical differentiation from arrow derived hematopoietic stem cells towards the monocytedendritic cells linages. Our research aims are: 1) Identifying the lineage specific repressor(s) mediating IRF-8 lineage restrictive expression. 2.) Characterization of the lineage specific regulatory network(s). 3) The role of cis- and trans- chromosomal interactions in modulating chromatin architecture leading to IRF-8 lineage specific expression.
7. Dror, N., Rave-Harel, A. Burchert, A. Azriel, T. Tamura, P. Tailor, A. Neubauer, K. Ozato, and B. Z. Levi. 2007. IRF-8 is indispensable for the expression of PML and the formation of nuclear bodies in myeloid cells. J Biol.Chem. 282:5633-5640.
8. Chermesh, I., A. Azriel, M. Alter-Koltunoff, R. Eliakim, A. Karban, and B. Z. Levi. 2007. Crohn’s Disease and SLC11A1 Promoter Polymorphism. Dig.Dis.Sci. 52:1632-1635.
9. Alter-Koltunoff, M., S. Goren, J. Nousbeck, C. G. Feng, A. Sher, K. Ozato, A. Azriel, and B. Z. Levi. 2008. Innate Immunity to Intraphagosomal Pathogens Is Mediated by Interferon Regulatory Factor 8 (IRF-8) That Stimulates the Expression of Macrophage-specific Nramp1 through Antagonizing Repression by c-Myc. J Biol.Chem. 283:2724-2733.
10. Lee, K. Y., H. Geng, K. M. Ng, J. Yu, A. van Hasselt, Y. Cao, Y. X. Zeng, A. H. Wong, X. Wang, J. Ying, G. Srivastava, M. L. Lung, L. D. Wang, T. T. Kwok, B. Z. Levi, A. T. Chan, J. J. Sung, and Q. Tao. 2008. Epigenetic disruption of interferon-gamma response through silencing the tumor suppressor interferon regulatory factor 8 in nasopharyngeal, esophageal and multiple other carcinomas. Oncogene, 27:5267–5276.
11. Khalfin-Rabinovich Y., Weinstein A., and B.Z. Levi. 2011. PML is a key component for the differentiation of myeloid progenitor cells to macrophages. Int Immunol. 23:287-296.