Epigenetic regulation of trained immunity

Section on Molecular Genetics of Immunity, Division of Developmental Biology, National Institute of Child Health and Human Development, National Institute of Health  


Research topic

This group is interested in epigenetic regulation of innate immunity, as it relates to transcription and chromatin. We study the activity of three key proteins, [1] DNA specific transcription factor IRF8, [2] Variant histone H3.3, [2] Chromatin reader BRD4. We investigate these factors in microglia (macrophage like cells in the brain) and peripheral and bone marrow-derived monocytes/macrophages. Their roles are tested in in inflammatory responses driven by interferon (IFN) and NFkB pathways. Our goal is to clarify how these proteins contribute to transcriptome and generate epigenetic memory. Currently, we work on interferon (IFN) induced innate immune memory in macrophages and embryonic fibroblasts. We focus on the role of the histone variant H3.3, as a follow-up of previous findings that H3.3 marks correlate well with IFN memory (1). In addition, we study LPS induced innate immune memory in microglia. We aim for establishing an in vivo model of training/memory relevant to neuroinflammation and neurodegenerative diseases.       


Group leader

Keiko Ozato, Ph.D 


Group members

Two senior scientists, 5 post-doctoral fellows and one post-bac student


Selected publications

  • Kamada, R., Yang, W., Zhang, Y., Patel, M. C., Yang, Y., Ouda, R., Dey, A., Wakabayashi, Y., Sakaguchi, K. Fujita, T., Tamura, T., Zhu, J., and Ozato, K. (2018) Interferon stimulation creates chromatin marks and establishes transcriptional memory. Proc Natl Acad Sci U S A 115, E9162-E9171
  • Dey, A., Yang, W., Gegonne, A., Nishiyama, A., Pan, R., Yagi, R., Grinberg, A., Finkelman, F. D., Pfeifer, K., Zhu, J., Singer, D., Zhu, J., and Ozato, K. (2019) BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses. EMBO J 38
  • Bachu, M., Tamura, T., Chen, C., Narain, A., Nehru, V., Sarai, N., Ghosh, S. B., Ghosh, A., Kavarthapu, R., Dufau, M. L., and Ozato, K. (2019) A versatile mouse model of epitope-tagged histone H3.3 to study epigenome dynamics. J Biol Chem 294, 1904-1914
  • Haque, N., Ouda, R., Chen, C., Ozato, K., and Hogg, J. R. (2018) ZFR coordinates crosstalk between RNA decay and transcription in innate immunity. Nat Commun 9, 1145
  • Kurotaki, D., Kawase, W., Sasaki, H., Nakabayashi, J., Nishiyama, A., Morse, H. C., 3rd, Ozato, K., Suzuki, Y., and Tamura, T. (2019) Epigenetic control of early dendritic cell lineage specification by the transcription factor IRF8 in mice. Blood 133, 1803-1813
  • Thumbigere-Math, V., Foster, B. L., Bachu, M., Yoshii, H., Brooks, S. R., Coulter, A., Chavez, M. B., Togi, S., Neely, A. L., Deng, Z., Mansky, K. C., Ozato, K., and Somerman, M. J. (2019) Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption. J Bone Miner Res 34, 1155-1168

Financial support

NICHD Intramural Research Grant, National Institutes of Health