Dissecting the regulatory strategies of NF-kB RelA target genes in the inflammatory response reveals differential transactivation logics

Ngo, Kim A, Kishimoto, Kensei, Davis-Turak, Jeremy, Pimplaskar, Aditya Pimplaskar, Cheng, Zhang, Spreafico, Roberto, Chen, Emily Y, Tam, Amy, Ghosh, Gourisankar, Mitchell, Simon and Hoffman, Alexander (2020) Dissecting the regulatory strategies of NF-kB RelA target genes in the inflammatory response reveals differential transactivation logics. Cell reports, 30 (8). pp. 2758-2775. ISSN 2211-1247

[img] PDF (Dissecting the Regulatory Strategies of NF-kB RelA Target Genes in the Inflammatory Response Reveals Differential Transactivation Logics) - Published Version
Available under License Creative Commons Attribution-NonCommercial No Derivatives.

Download (11MB)

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.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
Subjects: Q Science
Depositing User: Gemma Hamilton
Date Deposited: 22 Apr 2020 06:56
Last Modified: 22 Apr 2020 07:00
URI: http://sro.sussex.ac.uk/id/eprint/90963

View download statistics for this item

📧 Request an update