Kinetic proofreading of gene activation by chromatin remodeling

Blossey, Ralf; Schiessel, Helmut

doi:10.2976/1.2909080

Cited by 36 publications

(31 citation statements)

References 13 publications

(26 reference statements)

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“…In contrast to PCNA, ISWIs thoroughly probe a large number of nucleosomes by a continuous sampling mechanism, thus ensuring that potential targets are reliably identified. Interestingly, ISWI-type remodelers have been proposed to translocate nucleosomes according to a kinetic proof reading scheme, 35,36 which involves the cell cycle was followed by flow cytometry using a FACSCalibur instrument (BD Biosciences) after fixing the cells with ethanol and staining with 0.25 μM TO-PRO3 and an antibody against GFP. Data were analyzed with the software Weasel (WEHI).…”

Section: Methodsmentioning

confidence: 99%

Binding kinetics of human ISWI chromatin-remodelers to DNA repair sites elucidate their target location mechanism

Erdel

Rippe

2011

Nucleus

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Chromatin remodelers translocate nucleosomes along the DNA chain in an ATP-dependent manner. This catalytic activity is particularly important for DNA replication and repair since both processes require a significant amount of nucleosome translocations and assembly during DNA synthesis. Recently, we have studied the mobility and interactions of the human ISWI family chromatin remodelers Snf2H and Snf2L as well as Acf1, one of the non-catalytic subunits present in the ACF and CHRAC complexes of Snf2H. We proposed that these protein complexes identify their nucleosomal substrates via a continuous sampling mechanism. It rationalizes the relatively high nuclear mobility and abundance observed for all ISWI proteins in terms of fast target location. According to our model a certain type of ISWI complex visits a given nucleosome in the human genome on the timescale of several seconds to a few minutes. Here, we show that the ISWI proteins Snf2H, Snf2L as well as Acf1 accumulate at UV-induced DNA damage sites within tens of seconds and reach a plateau after a few minutes. These findings corroborate the predictions of the continuous sampling mechanism as an efficient way for targeting chromatin remodelers to sites in the genome that require their activity. In comparison to the mobility of PCNA (proliferating cell nuclear antigen) that also accumulates at DNA repair sites the specifics of substrate location by chromatin remodelers are further characterized.

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Section: Methodsmentioning

confidence: 99%

Binding kinetics of human ISWI chromatin-remodelers to DNA repair sites elucidate their target location mechanism

Erdel

Rippe

2011

Nucleus

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“…These modifications directly affect nucleosome dynamics or recruit enzyme complexes required for various functions (Kouzarides 2007). Posttranslational modifications may provide kinetic proofreading to reduce the error rate of gene activation (Blossey and Schiessel 2008). We searched for methylation, acetylation, phosphorylation, and other histone PTMs using UniProt (Wu et al 2006) and using Textpresso with the spatial relationship ontological category followed by manual curation (Muller et al 2004).…”

Section: Mutations Affecting Post-translational Modificationsmentioning

confidence: 99%

HistoneHits: A database for histone mutations and their phenotypes

Huang¹,

Maertens²,

Hyland³

et al. 2009

Genome Res.

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Histones are the basic protein components of nucleosomes. They are among the most conserved proteins and are subject to a plethora of post-translational modifications. Specific histone residues are important in establishing chromatin structure, regulating gene expression and silencing, and responding to DNA damage. Here we present HistoneHits, a database of phenotypes for systematic collections of histone mutants. This database combines assay results (phenotypes) with information about sequences, structures, post-translational modifications, and evolutionary conservation. The web interface presents the information through dynamic tables and figures. It calculates the availability of data for specific mutants and for nucleosome surfaces. The database currently includes 42 assays on 677 mutants multiply covering 405 of the 498 residues across yeast histones H3, H4, H2A, and H2B. We also provide an interface with an extensible controlled vocabulary for research groups to submit new data. Preliminary analyses confirm that mutations at highly conserved residues and modifiable residues are more likely to generate phenotypes. Buried residues and residues on the lateral surface tend to generate more phenotypes, while tail residues generate significantly fewer phenotypes than other residues. Yeast mutants are cross referenced with known human histone variants, identifying a position where a yeast mutant causes loss of ribosomal silencing and a human variant increases breast cancer susceptibility. All data sets are freely available for download.

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“…It has been suggested that both the SWI/SNF and ISWI/ACF chromatin remodelling complexes use an ATP-dependent kinetic proofreading scheme to find the correct nucleosomal substrates on which to act [59,60], in a manner essentially identical to Hopfield's original scheme [61]. In contrast, as mentioned in the Background, nucleosomes have been treated as competing with transcription factors for binding to DNA within the thermodynamic formalism, ignoring the dissipative aspects [18,62].…”

Section: Discussionmentioning

confidence: 99%

A framework for modelling gene regulation which accommodates non-equilibrium mechanisms

et al. 2014

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Background: Gene regulation has, for the most part, been quantitatively analysed by assuming that regulatory mechanisms operate at thermodynamic equilibrium. This formalism was originally developed to analyse the binding and unbinding of transcription factors from naked DNA in eubacteria. Although widely used, it has made it difficult to understand the role of energy-dissipating, epigenetic mechanisms, such as DNA methylation, nucleosome remodelling and post-translational modification of histones and co-regulators, which act together with transcription factors to regulate gene expression in eukaryotes.Results: Here, we introduce a graph-based framework that can accommodate non-equilibrium mechanisms. A gene-regulatory system is described as a graph, which specifies the DNA microstates (vertices), the transitions between microstates (edges) and the transition rates (edge labels). The graph yields a stochastic master equation for how microstate probabilities change over time. We show that this framework has broad scope by providing new insights into three very different ad hoc models, of steroid-hormone responsive genes, of inherently bounded chromatin domains and of the yeast PHO5 gene. We find, moreover, surprising complexity in the regulation of PHO5, which has not yet been experimentally explored, and we show that this complexity is an inherent feature of being away from equilibrium. At equilibrium, microstate probabilities do not depend on how a microstate is reached but, away from equilibrium, each path to a microstate can contribute to its steady-state probability. Systems that are far from equilibrium thereby become dependent on history and the resulting complexity is a fundamental challenge. To begin addressing this, we introduce a graph-based concept of independence, which can be applied to sub-systems that are far from equilibrium, and prove that history-dependent complexity can be circumvented when sub-systems operate independently. Conclusions: As epigenomic data become increasingly available, we anticipate that gene function will come to be represented by graphs, as gene structure has been represented by sequences, and that the methods introduced here will provide a broader foundation for understanding how genes work.

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Kinetic proofreading of gene activation by chromatin remodeling

Cited by 36 publications

References 13 publications

Binding kinetics of human ISWI chromatin-remodelers to DNA repair sites elucidate their target location mechanism

Binding kinetics of human ISWI chromatin-remodelers to DNA repair sites elucidate their target location mechanism

HistoneHits: A database for histone mutations and their phenotypes

A framework for modelling gene regulation which accommodates non-equilibrium mechanisms

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