- Keiko Ozato, Ph.D, P.I
- Anup Dey, Ph.D, Biologist
Keiko Ozato and her colleagues in the Section on Molecular Genetics of Immunity are interested in epigenetic gene regulation in innate immunity that relates to transcription and chromatin regulation. The current focus of this group is to study several key proteins that influence chromatin environment and gene expression. Their work centers on innate immune responses and analyze newly constructed mouse models. The proteins currently investigated by this group include  the replacement histone H3.3 that is incorporated into the genome through transcription, and HIRA, a chromatin assembly factor specific for H3.3,  BRD4, the bromodomain protein that binds to acetylated histones that regulates transcription, and  IRF8, the DNA binding transcription factor that promotes development of the innate immune system and is important for host resistance. Their aim is to clarify how these factors control transcriptional programs and affect epigenetic memory.
The group recently showed that when cells are stimulated by interferons (IFNs), histone H3.3 is deposited in interferon stimulated genes (ISGs) along with ISG transcription elongation. This H3.3 deposition requires BRD4, HIRA mentioned above and WHSC1, the histone methyltransferase. This deposition represents a long lasting epigenetic mark on ISGs. The H3.3 mark generated by IFN stimulation may create transcriptional memory that influences future innate immune functions. Unexpectedly, Ozato and associates found that IRF8 promotes demyelination and neuronal damage in the mouse model of multiple sclerosis (MS). IRF8 does this by giving TGF-beta signaling to T cells and activating microglia, cells that execute innate immune function in the brain. IRF8 has been known as a risk factor for MS, and their findings provide a mechanistic insight into its role in the disease. On the other hand, IRF8 is highly beneficial for the combatting infections. The group showed that IRF8 stimulates transcription of >20 genes important for autophagy in macrophages and dendritic cells, and it helps eliminate Listeria monocytogenes, the bacterium that causes disease in humans. They conclude that IRF8 is a master regulator of autophagy, and facilitates elimination of self and foreign wastes. Their next work will address how IRF8 controls autophagy and inflammation in brain microglia in health and disease.
- Gupta M, Shin DM, Ramakrishna L, Goussetis DJ, Platanias LC, Xiong H, Morse Iii HC, Ozato K. IRF8 directs stress-induced autophagy in macrophages and promotes clearance of Listeria monocytogenes. Nat Commun. 6:6379, 2015. PMID: 25775030
- Kanno T, Kanno Y, LeRoy G, Campos E, Sun HW, Brooks SR, Vahedi G, Heightman TD, Garcia BA, Reinberg D, Siebenlist U, O'Shea JJ, Ozato K. BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones. Nat Struct Mol Biol. 12:1047-1057 2014. PMID: 25383670
- Mancino A, Termanini A, Barozzi I, Ghisletti S, Ostuni R, Prosperini E, Ozato K, Natoli G. A dual cis-regulatory code links IRF8 to constitutive and inducible gene expression in macrophages. Genes Dev.29:394-408, 2015. PMID: 25636355
- Yoshida, Y., Yoshimi, R., Yoshii, Y., Kim, D., Dey, A., Xiong, H., Munasinghe, J., Yazawa, I., O’Donnovan, MJ., Maximova, OA., Wang, H., Morse, HC3rd, Ozato, K. IRF8 activates integrin-mediated TGFb signaling and promotes neuroinflammation. Immunity 40:187-198, 2014. PMID: 24485804
- Sarai, N., Nimura. K., Tamura. T., Kanno, T., Patel, M.C, Heightman,T.D., Ura, K, and Ozato, K. The Methyltransferase WHSC1 directs elongation and histone H3.3 deposition in interferon stimulated genes. EMBO.J 32: 2392-2406, 2013 PMID: 23921552
- Patel, M.C., Debrosse, M., Smith, M., Dey, A., Huynh, W., Heightman, T.D., Tamura, T and Ozato, K. BRD4 recruits the pausing complex NELF/DSIF along with P-TEFb to coordinate transcription elongation from interferon stimulated genes. Mol. Cell Biol. 33: 2497-2507, 2013. PMID: 23589332
- Kurotaki, D., Osato, N., Nishiyama, A., Yamamoto M., Ban T., Sato H., Nakabayashi. J., Umehara, M., Miyake, .N, Matsumoto N., Nakazawa,. M, Ozato, K., Tamura, T. Essential role of the IRF8-KLF4 transcription factor cascade in murine monocyte differentiation. Blood. 121:1839-1849, 2013, PMID: 23319570