Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading

Ido Goldstein (), Ville Paakinaho, Songjoon Baek, Myong-Hee Sung and Gordon L. Hager ()
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Ido Goldstein: Laboratory of Receptor Biology and Gene Expression, CCR, NCI, NIH
Ville Paakinaho: Laboratory of Receptor Biology and Gene Expression, CCR, NCI, NIH
Songjoon Baek: Laboratory of Receptor Biology and Gene Expression, CCR, NCI, NIH
Myong-Hee Sung: Laboratory of Molecular Biology and Immunology, NIA, NIH
Gordon L. Hager: Laboratory of Receptor Biology and Gene Expression, CCR, NCI, NIH

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract The cytokines interleukin 1β and 6 (IL-1β, IL-6) mediate the acute phase response (APR). In liver, they regulate the secretion of acute phase proteins. Using RNA-seq in primary hepatocytes, we show that these cytokines regulate transcription in a bifurcated manner, leading to both synergistic and antagonistic gene expression. By mapping changes in enhancer landscape and transcription factor occupancy (using ChIP-seq), we show that synergistic gene induction is achieved by assisted loading of STAT3 on chromatin by NF-κB. With IL-6 treatment alone, STAT3 does not efficiently bind 20% of its coordinated binding sites. In the presence of IL-1β, NF-κB is activated, binds a subset of enhancers and primes their activity, as evidenced by increasing H3K27ac. This facilitates STAT3 binding and synergistic gene expression. Our findings reveal an enhancer-specific crosstalk whereby NF-κB enables STAT3 binding at some enhancers while perturbing it at others. This model reconciles seemingly contradictory reports of NF-κB-STAT3 crosstalk.

Date: 2017
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DOI: 10.1038/s41467-017-02055-5

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