Chromobox Protein-7 (CBX7), a Polycomb Group Repressor, Functions as a Transcriptional Co-activator of Type 2 Cytokine Genes in Lymphoid Cells and is Important for Asthma

CBX7 is a H3K27 methyl reader and a polycomb repressor complex-1 (PRC1) member. Its role in cytokine gene expression is unknown. ChIP, Flow cytometry, gene knockdown, and mouse model of asthma CBX7 was identified as a steroid resistant gene in a functional genomic study. Airway lymphoid cells from a subgroup of asthmatic patients manifest steroid resistance. For this reason we examined CBX7 regulation of cytokine production. The pharmacologic inhibitor of CBX7—MS37452 blocked expression of cytokines—IL4, IL5, IL13, and IFN-γ by human blood lymphocytes and innate lymphoid cells suggesting an activating but not repressive function of CBX7. Likewise, shRNA-mediated knockdown of CBX7 inhibited cytokine expression by lymphocytes. To delineate the molecular mechanism we performed chromatin-Immunoprecipitation (ChIP) of activated lymphocytes, which showed binding of CBX7 to the proximal promoters, conserved non-coding sequences (CNS), and the enhancer region of the cytokine genes and GATA-3. CBX7 physically interacted with the transcriptional co-activators (histone acetyl transferase P300 and casein kinase-2) and polymerase-II in co-precipitation studies, which explained its co-activator function. To define its in vivo function we sensitized and challenged Rag1-/- mice with Alternaria. Pretreatment of mice with MS37452 but not with DMSO abrogated Alternaria-induced airway hyperreactivity and eosinophilic inflammation. MS37452 inhibited IL5 and IL13 production by steroid-resistant ILCs and lymphocytes from bronchoalveolar lavage obtained from asthma patients. CBX7, unexpectedly, functions as a transcriptional co-activator of cytokine genes. CBX7 binds to the promoter and enhancer of cytokines, and recruits transcriptional co-activators to facilitate gene transcription. CBX7 inhibitors are likely to benefit steroid-resistant asthma.