Chromatin provides major mechanisms of epigenetic regulation in mammals. Aberrant epigenetic regulation is frequently associated with diseases including cancer, immune disease. Interferons (IFN) are produced after viral or bacterial infection and inflammatory signals. In mammals, IFN provide the first line of defense against pathogens. IFNs stimulate transcription of more than 1,500 genes that are called IFN stimulated genes (ISGs). We found that the fibroblasts that had been stimulated IFN earlier were able to induce ISGs faster and at higher levels when they were restimulated by IFN. This process was regulated with a distinct chromatin state involving the histone H3.3 and H3K36 modifications (Fig.1). Our findings provide mechanistic framework for “trained innate immunity”.
We are also studying the role of Ser/Thr phosphatase PPM1D in regulation of immune cell differentiation and maturation. We are developing PPM1D selective inhibitors and new analysis techniques and tools for monitoring cell differentiation. The goal of our research is to understand the molecular mechanisms that regulate innate immune responses and trained innate immunity.