Dissecting the Regulatory Strategies of NF-κB RelA Target Genes in the Inflammatory Response Reveals Differential Transactivation Logics.

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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Ngo KA,Kishimoto K,Davis-Turak J,Pimplaskar A,Cheng Z,Spreafico R,Chen EY,Tam A,Ghosh G,Mitchell S,Hoffmann A

doi

10.1016/j.celrep.2020.01.108

subject

Has Abstract

pub_date

2020-02-25 00:00:00

pages

2758-2775.e6

issue

8

issn

2211-1247

pii

S2211-1247(20)30152-2

journal_volume

30

pub_type

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