S-19 : Epigenetic regulation of interferon response
Cytokine signaling changes the epigenetic status of the genome and influences gene expression patterns and function of the cells for generations. In the whole animal cells and tissues in vivo are often exposed to repeated cytokine stimulation in response to chronic infection and inflammation. Under these conditions cells previously stimulated with a specific cytokine may respond differently from cells that are stimulated for the first time. Relevant to this issue, type I interferons (IFNs) are administered by repeatedly injections to treat various diseases including Multiple Sclerosis. We previously showed that IFNs trigger de novo recruitment of RNA polymerase II and elongation factors to induce IFN stimulated genes (ISGs) mRNA. ISG induction results in a dramatic chromatin exchange involving histone H3.3, which in turn leaves a lasting epigenetic mark on ISGs (Patel, M. et al., MCB, 2013: Sarai, N. et al., EMBO J, 2013). We asked whether the epigenetic states generated by the first type I IFN stimulation affects cells’ ability to respond to IFNs subsequently. We show that cells that were exposed to IFNs before show different patterns of ISG mRNA induction from those of naive cells that were stimulated by IFNs for the first time. This led to noticeable alterations in cells’ anti-viral activity. The phenomenon observed with the second IFN stimulation is similar to “transcriptional memory” in the yeast models described for nutrient response genes. We present evidence that this epigenetic memory is linked to changes in the chromatin architecture of ISGs.