Keiko Ozato PhD

Keiko Ozato


Phone Numbers
  • Keiko Ozato, Ph.D, P.I
    (301) 496-9184
  • Anup Dey, Ph.D, Biologist
    (301) 496-4070

 

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 [1] the replacement histone H3.3 that is incorporated into the genome through transcription, and HIRA, a chromatin assembly factor specific for H3.3, [2] BRD4, the bromodomain protein that binds to acetylated histones that regulates transcription, and [3] 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.

Selected Publications

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