RNAi-Based Identification of Gene-Specific Nuclear Cofactor Networks Regulating Interleukin-1 Target Genes

• Published in: Frontiers in immunology 2018-04, Vol.9, p.775-775
• Main Authors: Meier-Soelch, Johanna, Jurida, Liane, Weber, Axel, Newel, Doris, Kim, Johnny, Braun, Thomas, Schmitz, M Lienhard, Kracht, Michael
• Format: Article
• Language: English
• Subjects: chromatin; coactivator; corepressor; IL-1; Immunology; NF-κB; transcription
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2018.00775

The potent proinflammatory cytokine interleukin (IL)-1 triggers gene expression through the NF-κB signaling pathway. Here, we investigated the cofactor requirements of strongly regulated IL-1 target genes whose expression is impaired in p65 NF-κB-deficient murine embryonic fibroblasts. By two independent small-hairpin (sh)RNA screens, we examined 170 genes annotated to encode nuclear cofactors for their role in mRNA expression and identified 22 factors that modulated basal or IL-1-inducible levels. The functions of 16 of these factors were validated for and further analyzed for their role in regulation of 10 additional IL-1 target genes by RT-qPCR. These data reveal that each inducible gene has its own (quantitative) requirement of cofactors to maintain basal levels and to respond to IL-1. Twelve factors ( , and ) have not been previously implicated in inflammatory cytokine functions. Bioinformatics analysis indicates that they are components of complex nuclear protein networks that regulate chromatin functions and gene transcription. Collectively, these data suggest that downstream from the essential NF-κB signal each cytokine-inducible target gene has further subtle requirements for individual sets of nuclear cofactors that shape its transcriptional activation profile.