CBX7, a polycomb repressor, functions as a methylation-dependent transcriptional activator and cytosolic signaling regulator in lymphoid cells

CBX7, a chromatin remodeler, typically functions as a gene repressor. We, unexpectedly, found that CBX7 robustly formed methylation-dependent transcriptional and signaling complexes, which induced gene transcription directly by binding to cytokine gene promoters. CBX7 translocated to the cytosol, and formed a methylation-dependent signaling complex with c-Raf, MEK1/2, and CK2-? to generate, and sustain ERK1/2 signaling. CBX7 is an allergen-inducible gene. Genetic and pharmacologic interventions established an essential role for CBX7 for production of cytokines by mouse and asthmatic patient T cells and ILC2s, and for induction of allergic inflammation in multiple mouse models of asthma. RNA-sequencing demonstrated a large-scale loss and gain in gene transcription in CBX7-/- T cells. The top downregulated pathways included cytokine-cytokine receptor interaction, asthma and T helper cell differentiation. CBX7 induction of the transcriptional activation complex and methylation of the ERK1/2 signalosome was specific for lymphoid cells as they were absent in epithelial cells. Our studies established a new paradigm of CBX7-generated methylation-dependent signaling complexes regulating inflammation. Overall design: anti-CD3/28 antibody-stimulated splenic CD4 T cells from CBX7+/+ and CBX7-/- mice. Cell samples were collected from a total of 8 mice (four mice per group) following stimulation for 6h.