Modelling Transcriptional Interference and DNA Looping in Gene Regulation

Dodd, Ian B.; Shearwin, Keith E.; Sneppen, Kim

doi:10.1016/j.jmb.2007.04.041

Cited by 19 publications

(40 citation statements)

References 36 publications

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“…Our preliminary data on reciprocal expression of the two genes [29] are in agreement with experimental data on transcriptional interference [31,46,47]. However, in this study we dissected the independent effects of TNFα and IL-1β on DNaseI and Trap 1 regulation.…”

Section: Discussionsupporting

confidence: 88%

TNFα Amplifies DNaseI Expression in Renal Tubular Cells while IL-1β Promotes Nuclear DNaseI Translocation in an Endonuclease-Inactive Form

2015

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We have demonstrated that the renal endonuclease DNaseI is up-regulated in mesangial nephritis while down-regulated during progression of the disease. To determine the basis for these reciprocal DNaseI expression profiles we analyse processes accounting for an early increase in renal DNaseI expression. Main hypotheses were that i. the mesangial inflammation and secreted pro-inflammatory cytokines directly increase DNaseI protein expression in tubular cells, ii. the anti-apoptotic protein tumor necrosis factor receptor-associated protein 1 (Trap 1) is down-regulated by increased expression of DNaseI due to transcriptional interference, and iii. pro-inflammatory cytokines promote nuclear translocation of a variant of DNaseI. The latter hypothesis emerges from the fact that anti-DNaseI antibodies stained tubular cell nuclei in murine and human lupus nephritis. The present study was performed on human tubular epithelial cells stimulated with pro-inflammatory cytokines. Expression of the DNaseI and Trap 1 genes was determined by qPCR, confocal microscopy, gel zymography, western blot and by immune electron microscopy. Results from in vitro cell culture experiments were analysed for biological relevance in kidneys from (NZBxNZW)F1 mice and human patients with lupus nephritis. Central data indicate that stimulating the tubular cells with TNFα promoted increased DNaseI and reduced Trap 1 expression, while TNFα and IL-1β stimulation induced nuclear translocation of the DNaseI. TNFα-stimulation resulted in 3 distinct effects; increased DNaseI and IL-1β gene expression, and nuclear translocation of DNaseI. IL-1β-stimulation solely induced nuclear DNaseI translocation. Tubular cells stimulated with TNFα and simultaneously transfected with IL-1β siRNA resulted in increased DNaseI expression but no nuclear translocation. This demonstrates that IL-1β promotes nuclear translocation of a cytoplasmic variant of DNaseI since translocation clearly was not dependent on DNaseI gene activation. Nuclear translocated DNaseI is shown to be enzymatically inactive, which may point at a new, yet unknown function of renal DNaseI.

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Section: Discussionsupporting

confidence: 88%

TNFα Amplifies DNaseI Expression in Renal Tubular Cells while IL-1β Promotes Nuclear DNaseI Translocation in an Endonuclease-Inactive Form

2015

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“…A number of examples of relief of TI, ranging from bacteriophages to fungi to mammals, involve developmental decisions (12,13,17–20). Our studies with the canonical λ system suggest clues as to why relief of TI may be particularly useful in cell fate choices.…”

Section: Discussionmentioning

confidence: 99%

“…Relief of TI by repression of the strong lytic promoter appears to be the primary mechanism for activation of the convergent lysogenic promoter by the immunity repressor proteins of P2-like bacteriophages (12,13). Repression of colicin genes by the E. coli LexA repressor relieves TI on expression of the convergent colicin immunity gene (14).…”

Section: Introductionmentioning

confidence: 99%

The role of repressor kinetics in relief of transcriptional interference between convergent promoters

et al. 2016

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Transcriptional interference (TI), where transcription from a promoter is inhibited by the activity of other promoters in its vicinity on the same DNA, enables transcription factors to regulate a target promoter indirectly, inducing or relieving TI by controlling the interfering promoter. For convergent promoters, stochastic simulations indicate that relief of TI can be inhibited if the repressor at the interfering promoter has slow binding kinetics, making it either sensitive to frequent dislodgement by elongating RNA polymerases (RNAPs) from the target promoter, or able to be a strong roadblock to these RNAPs. In vivo measurements of relief of TI by CI or Cro repressors in the bacteriophage λ PR–PRE system show strong relief of TI and a lack of dislodgement and roadblocking effects, indicative of rapid CI and Cro binding kinetics. However, repression of the same λ promoter by a catalytically dead CRISPR Cas9 protein gave either compromised or no relief of TI depending on the orientation at which it binds DNA, consistent with dCas9 being a slow kinetics repressor. This analysis shows how the intrinsic properties of a repressor can be evolutionarily tuned to set the magnitude of relief of TI.

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“…Indeed, different aspects of the approach presented here were demonstrated in organisms from bacteria11,12,13,14 and yeast7,8,15,16,17 to flies10 and mammals18,19.…”

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confidence: 99%

From DNA sequence to transcriptional behaviour: a quantitative approach

2009

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Complex transcriptional behaviors are encoded in the DNA sequences of gene regulatory regions. Advances in our understanding of these behaviors have been gained recently by quantitative models that describe how molecules such as transcription factors and nucleosomes interact with the genomic sequence. An emerging view is that every regulatory sequence is associated with a unique binding affinity landscape for each molecule and, consequently, with a unique set of molecule binding configurations and transcriptional outputs. We present a quantitative framework based on existing methods that unifies these ideas. This framework explains many experimental observations regarding the binding patterns of factors and nucleosomes, and the dynamics of transcriptional activation. It can also be used to model more complex phenomena such as transcriptional noise and the evolution of transcriptional regulation.Many cellular and organismal processes depend on the establishment of complex patterns of gene expression at precise times and spatial locations, with inaccuracies in carrying out such transcriptional programs often being deleterious and leading to disease. The information for directing such expression patterns is encoded in regulatory DNA sequences -for example, reporter genes attached directly to such regulatory sequences adopt the expression pattern of the endogenous gene 1,2,3 , and DNA binding and gene expression patterns of an entire human chromosome are essentially unchanged in mice that carry this human chromosome 4 .Given the centrality of transcriptional programs to many biological processes, a predictive and quantitative understanding of the transcriptional behaviors encoded by DNA sequences is highly desirable. Such an understanding would allow us to go beyond merely identifying the transcription factors and regulatory DNA elements that are involved, and replace the existing qualitative and phenomenological descriptions by a mechanistic view of the process that integrates the involved components into physically realistic mechanistic models. Indeed, our ability to quantitatively predict the behavior of a regulatory system is a useful objective measure of the extent to which we truly understand how the system works. At a more practical level, the ability to accurately predict transcriptional behaviors from DNA sequences should allow us to predict the effect that sequence variation among individuals in the population has on gene expression and thus on more complex phenotypes and disease; and it would allow for improved rational design of transgenes for biotechnology and gene therapy. NIH Public Access Author ManuscriptNat Rev Genet. Author manuscript; available in PMC 2009 August 3. Published in final edited form as:Nat Rev Genet. 2009 July ; 10(7): 443-456. doi:10.1038/nrg2591. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptRecent work has significantly advanced our understanding of how genomic sequences are translated into transcriptional outputs. Progress has been made possib...

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Modelling Transcriptional Interference and DNA Looping in Gene Regulation

Cited by 19 publications

References 36 publications

TNFα Amplifies DNaseI Expression in Renal Tubular Cells while IL-1β Promotes Nuclear DNaseI Translocation in an Endonuclease-Inactive Form

TNFα Amplifies DNaseI Expression in Renal Tubular Cells while IL-1β Promotes Nuclear DNaseI Translocation in an Endonuclease-Inactive Form

The role of repressor kinetics in relief of transcriptional interference between convergent promoters

From DNA sequence to transcriptional behaviour: a quantitative approach

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