CBX7 functions as a methylation-dependent inducer of gene transcription and regulator of cytosolic signaling in lymphoid cells

Chromobox protein-7 (CBX7) functions as a gene repressor. We, unexpectedly, found that CBX7 formed a methylation-dependent transcriptional complex, which induced gene transcription by binding to cytokine gene promoters. CBX7 translocated to the cytosol and formed a methylation-dependent signaling complex with c-Raf, MAPK (mitogen-activated protein kinase) kinase 1/2 (MEK1/2), and casein kinase-2 (CK2)–α to generate and sustain extracellular signal–regulated kinase 1/2 (ERK1/2) signaling. CBX7 is an allergen-inducible gene. Genetic and pharmacologic interventions established an essential role for CBX7 for the production of cytokines by mouse and asthmatic patient lymphoid cells, and for the induction of allergic asthma in multiple mouse models. RNA sequencing demonstrated a large-scale loss and gain in gene transcription in Cbx7 −/− T cells. The top down-regulated 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 previously unknown paradigm of CBX7-generated methylation-dependent signaling complexes regulating inflammation.