Stochastic resonances in a distributed genetic broadcasting system: the NF
            <i>κ</i>
            B/I
            <i>κ</i>
            B paradigm

Wang, Zhipeng; Potoyan, Davit A.; Wolynes, Peter G.

doi:10.1098/rsif.2017.0809

Cited by 3 publications

(3 citation statements)

References 26 publications

(42 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutation of the PEST interaction residues of IκB⍺ slows removal of NF-κB complexes from DNA and relocation of NF-κB from the nucleus ( Dembinski et al, 2017 ). Regulation of DNA binding/unbinding dynamics has been found to influence transcriptional response coherence ( Wang et al, 2018 ). These mechanisms of competition and molecular stripping may be broadly relevant in transcriptional regulation by other factors.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of IκB⍺ modulates NF-κB activation of inflammatory target gene expression

Downton

Bagnall

England

et al. 2023

Front. Mol. Biosci.

View full text Add to dashboard Cite

Cells respond to inflammatory stimuli such as cytokines by activation of the nuclear factor-κB (NF-κB) signalling pathway, resulting in oscillatory translocation of the transcription factor p65 between nucleus and cytoplasm in some cell types. We investigate the relationship between p65 and inhibitor-κB⍺ (IκBα) protein levels and dynamic properties of the system, and how this interaction impacts on the expression of key inflammatory genes. Using bacterial artificial chromosomes, we developed new cell models of IκB⍺-eGFP protein overexpression in a pseudo-native genomic context. We find that cells with high levels of the negative regulator IκBα remain responsive to inflammatory stimuli and maintain dynamics for both p65 and IκBα. In contrast, canonical target gene expression is dramatically reduced by overexpression of IκBα, but can be partially rescued by overexpression of p65. Treatment with leptomycin B to promote nuclear accumulation of IκB⍺ also suppresses canonical target gene expression, suggesting a mechanism in which nuclear IκB⍺ accumulation prevents productive p65 interaction with promoter binding sites. This causes reduced target promoter binding and gene transcription, which we validate by chromatin immunoprecipitation and in primary cells. Overall, we show how inflammatory gene transcription is modulated by the expression levels of both IκB⍺ and p65. This results in an anti-inflammatory effect on transcription, demonstrating a broad mechanism to modulate the strength of inflammatory response.

show abstract

Section: Discussionmentioning

confidence: 99%

Overexpression of IκB⍺ modulates NF-κB activation of inflammatory target gene expression

Downton

Bagnall

England

et al. 2023

Front. Mol. Biosci.

View full text Add to dashboard Cite

show abstract

“…It is well known that eukaryotic nuclei are rich in disordered proteins linked with transcription and chromatin architecture reorganization activities [19,20]. There have been several proposals of the functional roles that may include catalysis of biochemical reactions, noise buffering and inducing ultra-sensitive signals [21][22][23]. However, understanding the mechanistic picture that links phase separation to the functional gene regulatory processes inside the nucleus has remained elusive [22] due to heterogeneous, multiscale, and non-equilibrium nature of the nuclear environment [24].…”

Section: Introductionmentioning

confidence: 99%

Liquid–liquid phase separation driven compartmentalization of reactive nucleoplasm

Laghmach

Potoyan

2020

Phys. Biol.

Self Cite

View full text Add to dashboard Cite

The nucleus of eukaryotic cells harbors active and out of equilibrium environments conducive to diverse gene regulatory processes. On a molecular scale, gene regulatory processes take place within hierarchically compartmentalized sub-nuclear bodies. While the impact of nuclear structure on gene regulation is widely appreciated, it has remained much less clear whether and how gene regulation is impacting nuclear order itself. Recently, the liquid–liquid phase separation emerged as a fundamental mechanism driving the formation of biomolecular condensates, including membrane-less organelles, chromatin territories, and transcriptional domains. The transience and environmental sensitivity of biomolecular condensation are strongly suggestive of kinetic gene-regulatory control of phase separation. To better understand kinetic aspects controlling biomolecular phase-separation, we have constructed a minimalist model of the reactive nucleoplasm. The model is based on the Cahn–Hilliard formulation of ternary protein–RNA–nucleoplasm components coupled to non-equilibrium and spatially dependent gene expression. We find a broad range of kinetic regimes through an extensive set of simulations where the interplay of phase separation and reactive timescales can generate heterogeneous multi-modal gene expression patterns. Furthermore, the significance of this finding is that heterogeneity of gene expression is linked directly with the heterogeneity of length-scales in phase-separated condensates.

show abstract

“…Specifically, the nucleus of eukaryotes contains a large fraction of proteins that undergo phase separation, which and are linked with transcription and chromatin architecture reorganization activities [18]. There have been several proposals of the functional roles that may include catalysis of biochemical reactions, noise buffering and inducing ultrasensitive signals [19,20,21]. However, understanding the mechanistic picture that links phase separation to the functional gene regulatory processes inside the nucleus has remained elusive [20] due to heterogeneous, multi-scale, and non-equilibrium nature of the nuclear environment [22].…”

Section: Introductionmentioning

confidence: 99%

Liquid-liquid phase separation driven compartmentalization of reactive nucleoplasm

Laghmach

Potoyan

2020

Preprint

Self Cite

View full text Add to dashboard Cite

The nucleus of eukaryotic cells harbors active and out of equilibrium environments conducive to diverse gene regulatory processes. On a molecular scale, gene regulatory processes take place within hierarchically compartmentalized sub-nuclear bodies. While the impact of nuclear structure on gene regulation is widely appreciated, it has remained much less clear whether and how gene regulation is impacting nuclear order itself. Recently, the liquid-liquid phase separation emerged as a fundamental mechanism driving the formation of biomolecular condensates, including membrane-less organelles, chromatin territories, and transcriptional domains. The transience and environmental sensitivity of biomolecular condensation are strongly suggestive of kinetic gene-regulatory control of phase separation. To better understand kinetic aspects controlling biomolecular phase-separation, we have constructed a minimalist model of the reactive nucleoplasm. The model is based on the Cahn-Hilliard formulation of ternary protein-RNA-nucleoplasm components coupled to non-equilibrium and spatially dependent gene expression. We find a broad range of kinetic regimes through an extensive set of simulations where the interplay of phase separation and reactive timescales can generate heterogeneous multi-modal gene expression patterns. Furthermore, the significance of this finding is that heterogeneity of gene expression is linked directly with the heterogeneity of length-scales in phase-separated condensates.

show abstract

Stochastic resonances in a distributed genetic broadcasting system: the NF κ B/I κ B paradigm

Cited by 3 publications

References 26 publications

Overexpression of IκB⍺ modulates NF-κB activation of inflammatory target gene expression

Overexpression of IκB⍺ modulates NF-κB activation of inflammatory target gene expression

Liquid–liquid phase separation driven compartmentalization of reactive nucleoplasm

Liquid-liquid phase separation driven compartmentalization of reactive nucleoplasm

Contact Info

Product

Resources

About