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

Frontiers in Immunology
Johanna Meier-SoelchMichael Kracht

Abstract

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 Cxcl2 mRNA expression and identified 22 factors that modulated basal or IL-1-inducible Cxcl2 levels. The functions of 16 of these factors were validated for Cxcl2 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 (Epc1, H2afz, Kdm2b, Kdm6a, Mbd3, Mta2, Phf21a, Ruvbl1, Sin3b, Suv420h1, Taf1, and Ube3a) 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-ind...Continue Reading

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Citations

May 24, 2020·The FEBS Journal·James W WilsonSonia Rocha
Nov 30, 2018·International Journal of Molecular Medicine·Hongwei WangYong Ji

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Methods Mentioned

BETA
PCR
fluorescence microscopy
transfections
transfection
histone
nuclear translocation
ChIP
immunoprecipitation
ChIP-seq
RNA-seq

Software Mentioned

Match
STRING
Ensembl
Cytoscape
SigmaPlot11
Biomart

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