ORCID Profile
0000-0001-9820-3567
Current Organisation
IT University of Copenhagen
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Publisher: Public Library of Science (PLoS)
Date: 11-07-2008
Publisher: American Physical Society (APS)
Date: 08-12-2006
Publisher: IOP Publishing
Date: 04-06-2010
DOI: 10.1088/1478-3975/7/2/026010
Abstract: Cells can often choose among several stably heritable phenotypes. Ex les are the expressions of genes in eukaryotic cells where long chromosomal regions can adopt persistent and heritable silenced or active states that may be associated with positive feedback in dynamic modification of nucleosomes. We generalize this mechanism in terms of bistability associated with valleys in an epigenetic landscape. A transfer matrix method was used to rigorously follow the system through the disruptive process of cell ision. This combined treatment of noisy dynamics both between and during cell ision provides an efficient way to calculate the stability of alternative states in a broad range of epigenetic systems.
Publisher: Oxford University Press (OUP)
Date: 29-02-2016
DOI: 10.1093/NAR/GKW124
Publisher: Elsevier BV
Date: 03-2000
DOI: 10.1016/J.JMB.2004.11.075
Abstract: Interactions between RNA polymerases (RNAP) resulting from tandem or convergent arrangements of promoters can cause transcriptional interference, often with important consequences for gene expression. However, it is not known what factors determine the magnitude of interference and which mechanisms are likely to predominate in any situation. We therefore developed a mathematical model incorporating three mechanisms of transcriptional interference in bacteria: occlusion (in which passing RNAPs block access to the promoter), collisions between elongating RNAPs, and "sitting duck" interference (in which RNAP complexes waiting to fire at the promoter are removed by passing RNAP). The predictions of the model are in good agreement with a recent quantitative in vivo study of convergent promoters in E.coli. Our analysis predicts that strong occlusion requires the interfering promoter to be very strong. Collisions can also produce strong interference but only if the interfering promoter is very strong or if the convergent promoters are far apart (>200 bp). For moderate strength interfering promoters and short inter-promoter distances, strong interference is dependent on the sitting duck mechanism. Sitting duck interference is dependent on the relative strengths of the two promoters. However, it is also dependent on the "aspect ratio" (the relative rates of RNAP binding and firing) of the sensitive promoter, allowing promoters of equal strength to have very different sensitivities to transcriptional interference. The model provides a framework for using transcriptional interference to investigate various dynamic processes on DNA in vivo.
Publisher: American Physical Society (APS)
Date: 28-06-2016
Publisher: EMBO
Date: 2008
DOI: 10.1038/MSB.2008.21
Publisher: Elsevier BV
Date: 12-2011
DOI: 10.1016/J.JMB.2011.10.027
Abstract: Positive feedback in nucleosome modification has been proposed to allow large chromatin regions to exist stably and heritably in distinct expression states. However, modeling has shown that such epigenetic bistability requires that modifying enzymes recruited by nucleosomes are active on distant nucleosomes, potentially allowing uncontrollable spreading of modification. By modeling the silencing of mating-type loci in Saccharomyces cerevisiae, we show that a modification reaction that combines a long-range component and a locally acting component can provide bistability and can be blocked by simple barriers that interrupt the nucleosome chain. We find that robust containment of the silenced region could be achieved by the presence of a number of weak simple barriers in the surrounding chromatin and a limited capacity of the positive feedback reaction. In addition, we show that the state of the silenced region can be regulated by silencer elements acting only on neighboring nucleosomes. Thus, a relatively simple set of nucleosome-modifying enzymes and recognition domains is all that is needed to make chromatin-based epigenetics useful and safe.
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1016/J.JMB.2007.04.041
Abstract: We describe a hybrid statistical mechanical and dynamical approach for modelling the formation of closed, open and elongating complexes of RNA polymerase, the interactions of these polymerases to produce transcriptional interference, and the regulation of these processes by a DNA-binding and DNA-looping regulatory protein. As a model system, we have used bacteriophage 186, for which genetic, biochemical and structural studies have suggested that the CI repressor binds as a 14-mer to form alternative DNA-looped complexes, and activates lysogenic transcription indirectly by relieving transcriptional interference caused by the convergent lytic promoter. The modelling showed that the original mechanisms proposed to explain this relief of transcriptional interference are not consistent with the available in vivo reporter data. However, a good fit to the reporter data was given by a revised model that incorporates a novel predicted regulatory mechanism: that RNA polymerase bound at the lysogenic promoter protects itself from transcriptional interference by recruiting CI to the lytic promoter. This mechanism and various estimates of in vivo biochemical parameters for the 186 CI system should be testable. Our results demonstrate the power of mathematical modelling for the extraction of detailed biochemical information from in vivo data.
Publisher: American Society for Microbiology
Date: 15-11-2009
DOI: 10.1128/JVI.01057-09
Abstract: Phage lambda is among the simplest organisms that make a developmental decision. An infected bacterium goes either into the lytic state, where the phage particles rapidly replicate and eventually lyse the cell, or into a lysogenic state, where the phage goes dormant and replicates along with the cell. Experimental observations by P. Kourilsky are consistent with a single phage infection deterministically choosing lysis and double infection resulting in a stochastic choice. We argue that the phage are playing a “game” of minimizing the chance of extinction and that the shift from determinism to stochasticity is due to a shift from a single-player to a multiplayer game. Crucial to the argument is the clonal identity of the phage.
Publisher: American Society for Microbiology
Date: 29-10-2010
Abstract: Genes of prokaryotes and Archaea are often organized in cotranscribed groups, or operons. In contrast, eukaryotic genes are generally transcribed independently. Here we show that there is a substantial economic gain for the cell to cotranscribe genes encoding protein complexes because it synchronizes the fluctuations, or noise, in the levels of the different components. This correlation substantially reduces the shortfall in production of the complex. This benefit is relatively large in small cells such as bacterial cells, in which there are few mRNAs and proteins per cell, and is diminished in larger cells such as eukaryotic cells.
Publisher: Informa UK Limited
Date: 04-2015
Publisher: Oxford University Press (OUP)
Date: 27-11-2013
DOI: 10.1093/NAR/GKT1235
Abstract: Inheritance of 5-methyl cytosine modification of CpG (CG/CG) DNA sequences is needed to maintain early developmental decisions in vertebrates. The standard inheritance model treats CpGs as independent, with methylated CpGs maintained by efficient methylation of hemimethylated CpGs produced after DNA replication, and unmethylated CpGs maintained by an absence of de novo methylation. By stochastic simulations of CpG islands over multiple cell cycles and systematic s ling of reaction parameters, we show that the standard model is inconsistent with many experimental observations. In contrast, dynamic collaboration between CpGs can provide strong error-tolerant somatic inheritance of both hypermethylated and hypomethylated states of a cluster of CpGs, reproducing observed stable bimodal methylation patterns. Known recruitment of methylating enzymes by methylated CpGs could provide the necessary collaboration, but we predict that recruitment of demethylating enzymes by unmethylated CpGs strengthens inheritance and allows CpG islands to remain hypomethylated within a sea of hypermethylation.
Publisher: Public Library of Science (PLoS)
Date: 20-12-2010
Publisher: Public Library of Science (PLoS)
Date: 16-08-2012
Publisher: American Society for Microbiology
Date: 03-2012
DOI: 10.1128/JVI.07236-11
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.JMB.2009.09.053
Abstract: The behavior of living systems is dependent on large dynamical gene regulatory networks (GRNs). However, the functioning of even the smallest GRNs is difficult to predict. The bistable GRN of bacteriophage lambda is able to count to make a decision between lysis and lysogeny on the basis of the number of phages infecting the cell, even though replication of the phage genome eliminates this initial difference. By simulating the behavior of a large number of random transcriptional GRNs, we show that a surprising variety of GRNs can carry out this complex task, including simple CI-Cro-like mutual repression networks. Thus, our study extends the repertoire of simple GRNs. Counterintuitively, the major effect of the addition of CII-like regulation, generally thought to be needed for counting by lambda, was to improve the ability of the networks to complete a simulated prophage induction. Our study suggests that additional regulatory mechanisms to decouple Cro and CII levels may exist in lambda and that infection counting could be widespread among temperate bacteriophages, many of which contain CI-Cro-like circuits.
Publisher: Elsevier BV
Date: 05-2007
DOI: 10.1016/J.CELL.2007.02.053
Abstract: Chromosomal regions can adopt stable and heritable alternative states resulting in bistable gene expression without changes to the DNA sequence. Such epigenetic control is often associated with alternative covalent modifications of histones. The stability and heritability of the states are thought to involve positive feedback where modified nucleosomes recruit enzymes that similarly modify nearby nucleosomes. We developed a simplified stochastic model for dynamic nucleosome modification based on the silent mating-type region of the yeast Schizosaccharomyces pombe. We show that the mechanism can give strong bistability that is resistant both to high noise due to random gain or loss of nucleosome modifications and to random partitioning upon DNA replication. However, robust bistability required: (1) cooperativity, the activity of more than one modified nucleosome, in the modification reactions and (2) that nucleosomes occasionally stimulate modification beyond their neighbor nucleosomes, arguing against a simple continuous spreading of nucleosome modification.
Publisher: Public Library of Science (PLoS)
Date: 23-12-2005
Location: Norway
No related grants have been discovered for Kim Sneppen.