This section is interested in transcription factors that regulate the development of the immune system. IRF-8/ICSBP, a DNA specific transcription factor is essential for the development of macrophages and dendritic cells. In addition to their development, IRF-8 controls the expression of interferons and the IL-12 cytokine in these cells, thereby playing a critical role in the establishment of innate immunity. To address the mechanism of IRF-8 action, we performed photobleaching experiments. We show that IRF-8 is moving rapidly in the nucleus and scanning the entire genome by transiently binding to chromatin in macrophages and DCs. Further analysis showed that IRF-8 chromatin interactions are regulated by external cytokine signaling. This study opened a new way to study transcription in living immune cells. Another model we investigate deals with a bromodomain protein Brd4. This protein binds to acetylated chromatin and associates with chromosomes during mitosis. Brd4 is thought to play a role in epigenetic memory. We found that Brd4 interacts with P-TEFb, a Cdk9/CyclinT heterodimer that is essential for RNA polymerase II transcriptional elongation. By chromatin immunoprecipitation analysis of the HIV-1LTR reporter, we provided evidence that Brd4 recruits P-TEFb to the promoter to stimulate transcription. These studies have unraveled a previously unknown role for Brd4 in transcription.

Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2006
Total Cost
Indirect Cost
Name
U.S. National Inst/Child Hlth/Human Dev
Department
Type
DUNS #
City
State
Country
United States
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Umehara, Takashi; Nakamura, Yoshihiro; Wakamori, Masatoshi et al. (2010) Structural implications for K5/K12-di-acetylated histone H4 recognition by the second bromodomain of BRD2. FEBS Lett 584:3901-8
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Chang, Tsung-Hsien; Kubota, Toru; Matsuoka, Mayumi et al. (2009) Ebola Zaire virus blocks type I interferon production by exploiting the host SUMO modification machinery. PLoS Pathog 5:e1000493
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Cho, Won-Kyung; Zhou, Meisheng; Jang, Moon Kyoo et al. (2007) Modulation of the Brd4/P-TEFb interaction by the human T-lymphotropic virus type 1 tax protein. J Virol 81:11179-86
Gabriele, Lucia; Ozato, Keiko (2007) The role of the interferon regulatory factor (IRF) family in dendritic cell development and function. Cytokine Growth Factor Rev 18:503-10
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Kong, Hee Jeong; Anderson, D Eric; Lee, Chang Hoon et al. (2007) Cutting edge: autoantigen Ro52 is an interferon inducible E3 ligase that ubiquitinates IRF-8 and enhances cytokine expression in macrophages. J Immunol 179:26-30
Dror, Natalie; Rave-Harel, Naama; Burchert, Andreas et al. (2007) Interferon regulatory factor-8 is indispensable for the expression of promyelocytic leukemia and the formation of nuclear bodies in myeloid cells. J Biol Chem 282:5633-40
Ozato, Keiko; Uno, Kazuko; Iwakura, Yoichiro (2007) Another road to interferon: Yasuichi Nagano's journey. J Interferon Cytokine Res 27:349-52

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