NF-κB dynamics determine the stimulus specificity of epigenomic reprogramming in macrophages

Cheng, Quen J.; Ohta, Sho; Sheu, Katherine M.; Spreafico, Roberto; Adelaja, Adewunmi; Taylor, Brooks; Hoffmann, Alexander

doi:10.1126/science.abc0269

Cited by 112 publications

(121 citation statements)

References 59 publications

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“…In a transient stimulation protocol IκBα-deficient cells show enhanced expression of some genes 15 , as NFκB duration may be discriminated by a slow mRNA decay step or a slow chromatin step 26 . In the persistent stimulation protocol IκBα-deficient cells show NFκB-mediated eviction of many more nucleosomes and establishment of de novo enhancers 27 . However, whether the slowed and diminished NFκB activation observed in IκBα-deficient cells 15 , 24 , 28 affects gene expression has not been examined.…”

Section: Introductionmentioning

confidence: 99%

IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells

et al. 2021

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Inflammatory stimuli triggers the degradation of three inhibitory κB (IκB) proteins, allowing for nuclear translocation of nuclear factor-κB (NFκB) for transcriptional induction of its target genes. Of these three, IκBα is a well-known negative feedback regulator that limits the duration of NFκB activity. We sought to determine whether IκBα’s role in enabling or limiting NFκB activation is important for tumor necrosis factor (TNF)-induced gene expression in human breast cancer cells (MCF-7). Contrary to our expectations, many more TNF-response genes showed reduced induction than enhanced induction in IκBα knockdown cells. Mathematical modeling was used to investigate the underlying mechanism. We found that the reduced activation of some NFκB target genes in IκBα-deficient cells could be explained by the incoherent feedforward loop (IFFL) model. In addition, for a subset of genes, prolonged NFκB activity due to loss of negative feedback control did not prolong their transient activation; this implied a multi-state transcription cycle control of gene induction. Genes encoding key inflammation-related transcription factors, such as JUNB and KLF10, were found to be best represented by a model that contained both the IFFL and the transcription cycle motif. Our analysis sheds light on the regulatory strategies that safeguard inflammatory gene expression from overproduction and repositions the function of IκBα not only as a negative feedback regulator of NFκB but also as an enabler of NFκB-regulated stimulus-responsive inflammatory gene expression. This study indicates the complex involvement of IκBα in the inflammatory response to TNF that is induced by radiation therapy in breast cancer.

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Section: Introductionmentioning

confidence: 99%

IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells

et al. 2021

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“…Since A20 mediates negative feedback on TLR and MAVS responses 49 , 50 , this may condition macrophages to undergo an exaggerated response to TLR ligands. A recent study has shown that loss of feedback suppression of NF-κB signaling as would occur with repression of A20, dampens oscillatory NF-κB signaling and sets the stage for increased expression of inflammatory genes as a result of epigenetic reprogramming 51 . Further unraveling of these interconnected pathways could advance the understanding of Sars-Cov-2 pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the NLRP3 inflammasome by Sars-CoV-2 Envelope protein

Yalçinkaya

Liu

Islam

et al. 2021

Sci Rep

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Despite the initial success of some drugs and vaccines targeting COVID-19, understanding the mechanism underlying SARS-CoV-2 disease pathogenesis remains crucial for the development of further approaches to treatment. Some patients with severe Covid-19 experience a cytokine storm and display evidence of inflammasome activation leading to increased levels of IL-1β and IL-18; however, other reports have suggested reduced inflammatory responses to Sars-Cov-2. In this study we have examined the effects of the Sars-Cov-2 envelope (E) protein, a virulence factor in coronaviruses, on inflammasome activation and pulmonary inflammation. In cultured macrophages the E protein suppressed inflammasome priming and NLRP3 inflammasome activation. Similarly, in mice transfected with E protein and treated with poly(I:C) to simulate the effects of viral RNA, the E protein, in an NLRP3-dependent fashion, reduced expression of pro-IL-1β, levels of IL-1β and IL-18 in broncho-alveolar lavage fluid, and macrophage infiltration in the lung. To simulate the effects of more advanced infection, macrophages were treated with both LPS and poly(I:C). In this setting the E protein increased NLRP3 inflammasome activation in both murine and human macrophages. Thus, the Sars-Cov-2 E protein may initially suppress the host NLRP3 inflammasome response to viral RNA while potentially increasing NLRP3 inflammasome responses in the later stages of infection. Targeting the Sars-Cov-2 E protein especially in the early stages of infection may represent a novel approach to Covid-19 therapy.

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“…Alternatively, as it was recently demonstrated for the Bicoid activator Hannon et al ( 2017 ), Dorsal could also have a pioneering activity. Indeed, the Dorsal homolog NF- ,c B has been recently shown to displace nucleosomes ( Cheng et al, 2021 ). To further test the kinetic barrier model, it would be informative to directly perturb the temporal dynamics of nuclear Dorsal concentration to affect transcriptional engagement.…”

Section: Discussionmentioning

confidence: 99%

Minimal synthetic enhancers reveal control of the probability of transcriptional engagement and its timing by a morphogen gradient

Reimer

Álamos

Westrum

et al. 2021

Preprint

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How enhancers interpret morphogen gradients to generate spatial patterns of gene expression is a central question in developmental biology. Although recent studies have begun to elucidate that enhancers can dictate whether, when, and at what rate a promoter will engage in transcription, the complexity of endogenous enhancers calls for theoretical models with too many free parameters to quantitatively dissect these regulatory strategies. To overcome this limitation, we established a minimal synthetic enhancer system in embryos of the fruit 2y Drosophila melanogaster. Here, a gradient of the Dorsal activator is read by a single Dorsal binding site. By quantifying transcriptional activity using live imaging, our experiments revealed that this single Dorsal binding site is capable of regulating whether promoters engage in transcription in a Dorsal concentration-speci1c manner. By modulating binding-site aZnity, we determined that a gene’s decision to engage in transcription and its transcriptional onset time can be explained by a simple theoretical model where the promoter has to traverse multiple kinetic barriers before transcription can ensue. The experimental platform developed here pushes the boundaries of live-imaging in studying gene regulation in the early embryo by enabling the quanti1cation of the transcriptional activity driven by a single transcription factor binding site, and making it possible to build more complex enhancers from the ground up in the context of a dialogue between theory and experiment.

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NF-κB dynamics determine the stimulus specificity of epigenomic reprogramming in macrophages

Cited by 112 publications

References 59 publications

IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells

IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells

Modulation of the NLRP3 inflammasome by Sars-CoV-2 Envelope protein

Minimal synthetic enhancers reveal control of the probability of transcriptional engagement and its timing by a morphogen gradient

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