Dissecting the regulatory strategies of NF-kB RelA target genes in the inflammatory response reveals differential transactivation logics
journal contributionposted on 2023-06-09, 21:09 authored by Kim A Ngo, Kensei Kishimoto, Jeremy Davis-Turak, Aditya Pimplaskar Pimplaskar, Zhang Cheng, Roberto Spreafico, Emily Y Chen, Amy Tam, Gourisankar Ghosh, Simon MitchellSimon Mitchell, Alexander Hoffman
Nuclear factor ?B (NF-?B) RelA is the potent transcriptional activator of inflammatory response genes. We stringently defined a list of direct RelA target genes by integrating physical (chromatin immunoprecipitation sequencing [ChIP-seq]) and functional (RNA sequencing [RNA-seq] in knockouts) datasets. We then dissected each gene’s regulatory strategy by testing RelA variants in a primary-cell genetic-complementation assay. All endogenous target genes require RelA to make DNA-base-specific contacts, and none are activatable by the DNA binding domain alone. However, endogenous target genes differ widely in how they employ the two transactivation domains. Through model-aided analysis of the dynamic time-course data, we reveal the gene-specific synergy and redundancy of TA1 and TA2. Given that post-translational modifications control TA1 activity and intrinsic affinity for coactivators determines TA2 activity, the differential TA logics suggests context-dependent versus context-independent control of endogenous RelA-target genes. Although some inflammatory initiators appear to require co-stimulatory TA1 activation, inflammatory resolvers are a part of the NF-?B RelA core response.
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