Toward an Understanding of the Gene-Specific and Global Logic of Inducible Gene Transcription

Smale, Stephen T.; Plevy, Scott E.; Weinmann, Amy S.; Zhou, Liang; Ramirez-Carrozzi, Vladimir; Pope, Scott D.; Bhatt, Dev; Tong, And Ann Jay

doi:10.1101/sqb.2013.78.020313

Cited by 6 publications

(6 citation statements)

References 42 publications

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“…In general, these results point to a model in which inactive genes are much more susceptible to transcription attenuation by low temperature than genes actively being transcribed. Potentially, chromatin remodeling around inducible promoters and initial assembly of transcription machinery represent additional obstacles to inducible genes being “turned on” that are absent from constitutively active genes ( 52 ). In addition, variation in the chromatin environments around different promoters, as well as in the transcription factors required for transcription of different genes, would allow for differential temperature sensitivity of inducible genes.…”

Section: Discussionmentioning

confidence: 99%

“…In this view, the reliable temperature sensitivity that we observed with ISGs is consistent with the presumption that IFN-stimulated response element (ISRE)-containing promoters reliant on similar transcription factors and chromatin modifications ( 54 – 56 ) would be subject to the same challenges of transcription initiation at subnormal temperatures, yielding the phenotype of temperature-sensitive ISG transcription. In contrast, the chromatin remodeling events and transcription factors required for LPS-responsive genes can vary considerably ( 52 , 57 ), allowing for the possibility of different effects of temperature shift on individual genes or subsets of genes. Consistent with this idea, several genes that responded to both LPS and IFN-α/β treatment followed the same temperature-dependent expression patterns regardless of the stimulus.…”

Section: Discussionmentioning

confidence: 99%

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The Efficacy of the Interferon Alpha/Beta Response versus Arboviruses Is Temperature Dependent

Lane

Dunn

Gardner

et al. 2018

mBio

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Interferon alpha/beta (IFN-α/β) is a critical mediator of protection against most viruses, with host survival frequently impossible in its absence. Many studies have investigated the pathways involved in the induction of IFN-α/β after virus infection and the resultant upregulation of antiviral IFN-stimulated genes (ISGs) through IFN-α/β receptor complex signaling. However, other than examining the effects of genetic deletion of induction or effector pathway components, little is known regarding the functionality of these responses in intact hosts and whether host genetic or environmental factors might influence their potency. Here, we demonstrate that the IFN-α/β response against multiple arthropod-vectored viruses, which replicate over a wide temperature range, is extremely sensitive to fluctuations in temperature, exhibiting reduced antiviral efficacy at subnormal cellular temperatures and increased efficacy at supranormal temperatures. The effect involves both IFN-α/β and ISG upregulation pathways with a major aspect of altered potency reflecting highly temperature-dependent transcription of IFN response genes that leads to altered IFN-α/β and ISG protein levels. Discordantly, signaling steps prior to transcription that were examined showed the opposite effect from gene transcription, with potentiation at low temperature and inhibition at high temperature. Finally, we demonstrate that by lowering the temperature of mice, chikungunya arbovirus replication and disease are exacerbated in an IFN-α/β-dependent manner. This finding raises the potential for use of hyperthermia as a therapeutic modality for viral infections and in other contexts such as antitumor therapy. The increased IFN-α/β efficacy at high temperatures may also reflect an innate immune-relevant aspect of the febrile response.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Efficacy of the Interferon Alpha/Beta Response versus Arboviruses Is Temperature Dependent

Lane

Dunn

Gardner

et al. 2018

mBio

View full text Add to dashboard Cite

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“…Cell-type specific regulatory circuits control gene expression in complex, dynamic and temporally regulated manners (Smale et al, 2013). Understanding these regulatory networks is critical for a better understanding of the biological processes that contribute to human health and disease.…”

Section: Introductionmentioning

confidence: 99%

A Long Noncoding RNA lincRNA-EPS Acts as a Transcriptional Brake to Restrain Inflammation

Atianand

Satpathy

et al. 2016

Cell

398

360

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SUMMARY Long intergenic noncoding RNAs (lincRNA) are important regulators of gene expression. Although lincRNAs are expressed in immune cells, their functions in immunity are largely unexplored. Here we identify an immunoregulatory lincRNA, lincRNA-EPS, that is precisely regulated in macrophages to control the expression of immune response genes (IRGs). Transcriptome analysis of macrophages from lincRNA-EPS-deficient mice, combined with gain-of-function and rescue experiments, revealed a specific role for this lincRNA in restraining IRG expression. Consistently, lincRNA-EPS-deficient mice manifest enhanced inflammation and lethality following endotoxin challenge in vivo. lincRNA-EPS associates with chromatin at regulatory regions of IRGs to control nucleosome positioning and repress transcription. Further, lincRNA-EPS mediates these effects by interacting with heterogeneous nuclear ribonucleoprotein L via a CANACA motif located in its 3′ end. Together, these findings identify lincRNA-EPS as a repressor of inflammatory responses highlighting the importance of lincRNAs in the immune system.

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“…The same gene is present in these cells but it may be difficult to know whether the corresponding regulatory machineries are also the same. More directly suitable examples for the present discussion arise in individual cells exposed to distinct stimuli (Molina et al, 2013, Kalo et al, 2015, Lin et al, 2015, which may be particularly the case for neurons or cells of the immune system (Marco et al, 2020, Smale et al, 2013.…”

Section: Discussionmentioning

confidence: 99%

Allosteric conformational ensembles have unlimited capacity for integrating information

Biddle

Martinez-Corral

Wong

et al. 2020

Preprint

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Integration of binding information by macromolecular entities is fundamental to cellular functionality. Recent work has shown that such integration cannot be explained by pairwise cooperativities, in which binding is modulated by binding at another site. Higher-order cooperativities (HOCs), in which binding is collectively modulated by multiple other binding events, appears to be necessary but an appropriate mechanism has been lacking. We show here that HOCs arise through allostery, in which effective cooperativity emerges indirectly from an ensemble of dynamically-interchanging conformations. Conformational ensembles play important roles in many cellular processes but their integrative capabilities remain poorly understood. We show that sufficiently complex ensembles can implement any form of information integration achievable without energy expenditure, including all HOCs. Our results provide a rigorous biophysical foundation for analysing the integration of binding information through allostery. We discuss the implications for eukaryotic gene regulation, where complex conformational dynamics accompanies widespread information integration.

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Toward an Understanding of the Gene-Specific and Global Logic of Inducible Gene Transcription

Cited by 6 publications

References 42 publications

The Efficacy of the Interferon Alpha/Beta Response versus Arboviruses Is Temperature Dependent

The Efficacy of the Interferon Alpha/Beta Response versus Arboviruses Is Temperature Dependent

A Long Noncoding RNA lincRNA-EPS Acts as a Transcriptional Brake to Restrain Inflammation

Allosteric conformational ensembles have unlimited capacity for integrating information

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