Education

PhD, Karolinska Institute, 2013

Lab information

Dr. Keiko Ozato's lab studies the gene regulation in innate immunity

Macrophages and dendritic cells (DC) respond to pathogen stimuli and produce cytokines including interferons (IFNs), IL-1, IL-6, and TNF-alpha to impart anti-viral and anti-microbial status to the host. The goal of our lab is to study molecular pathways that direct the development and function of macrophages and DCs. Our long-term interest has been the role of a transcription factor IRF8 in innate immunity. IRF8 is expressed in M_ and DC at high levels and is required for production of both type I and type II IFNs. IRF8 and related transcription factors including IRF3 and IRF7 are post-translationally modified by ubiquitin and small ubiquitin-like molecules (SUMO). SUMO modification of these factors almost always results in transcriptional repression. SUMO–mediated repression likely represents an important mechanism to limit overproduction of inflammatory cytokines.

Transcriptionally active genes are embedded in chromatin that is dynamically exchanged, whereas silenced genes are surrounded by more stable chromatin. The chromatin environment influences transcriptional processes and controls epigenetic regulation. We are interested in BRD4, a chromatin-binding protein associated with transcribed genes. We are also interested in histone H3.3, the variant histone that is selectively associated with actively expressed genes. BRD4 is a 200 kDa nuclear protein carrying two tandem bromodomains through which it binds to acetylated chromatin. BRD4 also interacts with the elongation factor P-TEFb and regulates transcription of many genes, including those induced by external stimuli. BRD4 is implicated in transcriptional memory across cell division because it stays on condensed chromosomes during mitosis and affects gene expression in the daughter cells. Despite close structural similarity with the standard H3.1 and H3.2, histone H3.3 has an extraordinary property, in that it is incorporated into nucleosomes and DNA only in actively transcribed genes. In contrast, H3.1, H3.2, and other standard core histones are incorporated into nucleosomes during DNA replication. The difference between H3.3 and H3.1/2 reflects distinct chromatin activities during replication and transcription. Although there is mounting recognition of the importance of transcription-coupled histone incorporation, the process and its physiological significance is still shrouded in mystery. Our goal is to elucidate the activity of BRD4 and histone H3.3 in the context of transcriptional activation and epigenetic memory.
https://irp.nih.gov/pi/keiko-ozato

Publications