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Polycomb repressive complex 2 is a critical mediator of allergic inflammation
Christine R. Keenan, … , Stephen L. Nutt, Rhys S. Allan
Christine R. Keenan, … , Stephen L. Nutt, Rhys S. Allan
Published May 16, 2019
Citation Information: JCI Insight. 2019;4(10):e127745. https://doi.org/10.1172/jci.insight.127745.
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Research Article Immunology Inflammation

Polycomb repressive complex 2 is a critical mediator of allergic inflammation

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Abstract

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.

Authors

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

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Figure 1

Components of the PRC2 and Suv39h/HP1 pathways are specifically upregulated after T cell activation.

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Components of the PRC2 and Suv39h/HP1 pathways are specifically upregula...
(A) Quantitation of the expression changes of the genes encoding 34 repressive chromatin components associated with histone modification from publicly available human CD4+ T cell microarray data (naive vs. 24-hour activation with anti-CD3 and anti-CD28) (11). Genes significantly upregulated are denoted in red, genes significantly downregulated are denoted in blue, and genes not significantly altered are denoted in black. Other genes are denoted in gray. (B) Representative Western blots of naive versus 24-hour-activated (anti-CD3 and anti-CD28) C57BL/6 mouse CD4+ T cells (biological replicates shown) with quantification (mean ± SEM with individual data points from 4 samples) shown (C). Statistical significance was determined by 2-way ANOVA with Holm-Sidak post hoc test. (D) Schematic displaying the molecules involved in the H3K27me3-associated PRC2 and H3K9me3-associated Suv39h/HP1 gene silencing.

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