1. Dissecting the Regulatory Strategies of NF-κB RelA Target Genes in the Inflammatory Response Reveals Differential Transactivation Logics
- Author
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Ngo, Kim A, Kishimoto, Kensei, Davis-Turak, Jeremy, Pimplaskar, Aditya, Cheng, Zhang, Spreafico, Roberto, Chen, Emily Y, Tam, Amy, Ghosh, Gourisankar, Mitchell, Simon, and Hoffmann, Alexander
- Subjects
Biotechnology ,Human Genome ,Genetics ,1.1 Normal biological development and functioning ,Underpinning research ,Generic health relevance ,Animals ,Base Sequence ,Embryo ,Mammalian ,Fibroblasts ,Inflammation ,Logic ,Mice ,Inbred C57BL ,Models ,Biological ,Protein Domains ,Transcription Factor RelA ,Transcriptional Activation ,Tumor Necrosis Factor-alpha ,NF-kappaB ,NF-κB ,gene regulatory strategies ,immune response ,inflammatory response ,mathematical modeling ,structure-function analysis ,systems biology ,transcriptional activation ,transcriptional synergy ,Biochemistry and Cell Biology ,Medical Physiology - Abstract
Nuclear factor κB (NF-κB) 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-κB RelA core response.
- Published
- 2020