Strategies that intervene with the development of immune-mediated diseases are urgently needed, as current treatments mostly focus on alleviating symptoms rather than reversing the disease. Targeting enzymes involved in epigenetic modifications to chromatin represents an alternative strategy that has the potential to perturb the function of the lymphocytes that drive the immune response. Here, we report that 2 major epigenetic silencing pathways are increased after T cell activation. By specific inactivation of these molecules in the T cell compartment in vivo, we demonstrate that the polycomb repressive complex 2 (PRC2) is essential for the generation of allergic responses. Furthermore, we show that small-molecule inhibition of the PRC2 methyltransferase, enhancer of zeste homolog 2 (Ezh2), reduces allergic inflammation in mice. Therefore, by systematically surveying the pathways involved in epigenetic gene silencing we have identified Ezh2 as a target for the suppression of allergic disease.
Christine R. Keenan, Nadia Iannarella, Alexandra L. Garnham, Alexandra C. Brown, Richard Y. Kim, Jay C. Horvat, Philip M. Hansbro, Stephen L. Nutt, Rhys S. Allan
Components of the PRC2 and Suv39h/HP1 pathways are specifically upregulated after T cell activation.