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Transcriptional outcomes and kinetic patterning of gene expression in response to NF-?B activation.

ABSTRACT: Transcription factor nuclear factor kappa B (NF-?B) regulates cellular responses to environmental cues. Many stimuli induce NF-?B transiently, making time-dependent transcriptional outputs a fundamental feature of NF-?B activation. Here we show that NF-?B target genes have distinct kinetic patterns in activated B lymphoma cells. By combining RELA binding, RNA polymerase II (Pol II) recruitment, and perturbation of NF-?B activation, we demonstrate that kinetic differences amongst early- and late-activated RELA target genes can be understood based on chromatin configuration prior to cell activation and RELA-dependent priming, respectively. We also identified genes that were repressed by RELA activation and others that responded to RELA-activated transcription factors. Cumulatively, our studies define an NF-?B-responsive inducible gene cascade in activated B cells.

SUBMITTER: Zhao M

PROVIDER: S-EPMC6147668 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Transcriptional outcomes and kinetic patterning of gene expression in response to NF-κB activation.

Zhao Mingming M Joy Jaimy J Zhou Weiqiang W De Supriyo S Wood William H WH Becker Kevin G KG Ji Hongkai H Sen Ranjan R

PLoS biology 20180910 9

Transcription factor nuclear factor kappa B (NF-κB) regulates cellular responses to environmental cues. Many stimuli induce NF-κB transiently, making time-dependent transcriptional outputs a fundamental feature of NF-κB activation. Here we show that NF-κB target genes have distinct kinetic patterns in activated B lymphoma cells. By combining RELA binding, RNA polymerase II (Pol II) recruitment, and perturbation of NF-κB activation, we demonstrate that kinetic differences amongst early- and late- ...[more]

PMID: 30199532

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Project description:The nuclear factor kappa B (NF-κB) pathway is known to integrate signaling associated with very diverse intra- and extracellular stressors, including virus infections, and triggers a powerful (proinflammatory) response through the expression of NF-κB-regulated genes. Typically, the NF-κB pathway collects and transduces threatening signals at the cell surface or in the cytoplasm leading to nuclear import of activated NF-κB transcription factors. In the current work, we demonstrate that the swine alphaherpesvirus pseudorabies virus (PRV) induces a peculiar mode of NF-κB activation known as "inside-out" NF-κB activation. We show that PRV triggers the DNA damage response (DDR) and that this DDR response drives NF-κB activation since inhibition of the nuclear ataxia telangiectasia-mutated (ATM) kinase, a chief controller of DDR, abolished PRV-induced NF-κB activation. Initiation of the DDR-NF-κB signaling axis requires viral protein synthesis but occurs before active viral genome replication. In addition, the initiation of the DDR-NF-κB signaling axis is followed by a virus-induced complete shutoff of NF-κB-dependent gene expression that depends on viral DNA replication. In summary, the results presented in this study reveal that PRV infection triggers a noncanonical DDR-NF-κB activation signaling axis and that the virus actively inhibits the (potentially antiviral) consequences of this pathway, by inhibiting NF-κB-dependent gene expression. IMPORTANCE The NF-κB signaling pathway plays a critical role in coordination of innate immune responses that are of vital importance in the control of infections. The current report generates new insights into the interaction of the alphaherpesvirus pseudorabies virus (PRV) with the NF-κB pathway, as they reveal that (i) PRV infection leads to NF-κB activation via a peculiar "inside-out" nucleus-to-cytoplasm signal that is triggered via the DNA damage response (DDR), (ii) the DDR-NF-κB signaling axis requires expression of viral proteins but is initiated before active PRV replication, and (iii) late viral factor(s) allow PRV to actively and efficiently inhibit NF-κB-dependent (proinflammatory) gene expression. These data suggest that activation of the DDR-NF-κB during PRV infection is host driven and that its potential antiviral consequences are actively inhibited by the virus.

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Transcriptional outcomes and kinetic patterning of gene expression in response to NF-?B activation.

Publications

Transcriptional outcomes and kinetic patterning of gene expression in response to NF-κB activation.

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