Nucleosome positioning and kinetics near transcription-start-site barriers are controlled by interplay between active remodeling and DNA sequence

Parmar, Jyotsana J.; Marko, John F.; Padinhateeri, Ranjith

doi:10.1093/nar/gkt854

Cited by 34 publications

(51 citation statements)

References 44 publications

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“…We incorporated the effect of these proteins as an energetic barrier centered at 150 bp upstream of TSS to penalize nucleosome formation. Similar treatment has been used by Padinhateeri and coworkers to create a nucleosomefree region near TSS (39). As illustrated in Figure 2B, the barrier is symmetric with respect to the center.…”

Section: Methodsmentioning

confidence: 71%

On the role of transcription in positioning nucleosomes

Jiang

Zhang

2020

Preprint

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Nucleosome positioning is crucial for the genome's function. Though the role of DNA sequence in positioning nucleosomes is well understood, a unified framework for studying the impact of transcription remains lacking. Using numerical simulations, we investigated the dependence of nucleosome density profiles on transcription level across multiple species. We found that the low nucleosome affinity of yeast, but not mouse, promoters contributes to the formation of phased nucleosomes arrays for inactive genes. For the active genes, a tug-of-war between two types of remodeling enzymes is essential for reproducing their density profiles. In particular, while ISW2 related enzymes are known to position the +1 nucleosome and align it toward the transcription start site (TSS), enzymes such as ISW1 that use a pair of nucleosomes as their substrate can shift the nucleosome array away from the TSS. Competition between these enzymes results in two types of nucleosome density profiles with well-and ill-positioned +1 nucleosome. Finally, we showed that Pol II assisted histone exchange, if occurring at a fast speed, can abolish the impact of remodeling enzymes. By elucidating the role of individual factors, our study reconciles the seemingly conflicting results on the overall impact of transcription in positioning nucleosomes across species.

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Section: Methodsmentioning

confidence: 71%

On the role of transcription in positioning nucleosomes

Jiang

Zhang

2020

Preprint

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“…Furthermore, subsequent experimental work of Celona et al [30] showed that only weak nucleosomes are being removed upon core histone depletion, while strong nucleosomes remain at their places, effectively keeping the NRL independent of the core histone concentration. In line with this, the authors of a recent Monte Carlo simulation hypothesize that DNA sequence-specific effects have the primary role on nucleosome positioning near TSSs [72]. To check this hypothesis in a more general context, we have utilized the nucleosome positioning data measured by MNase-seq for mouse embryonic stem cells (mESCs) [28].…”

Section: Resultsmentioning

confidence: 97%

Regulation of the Nucleosome Repeat Length In Vivo by the DNA Sequence, Protein Concentrations and Long-Range Interactions

et al. 2014

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The nucleosome repeat length (NRL) is an integral chromatin property important for its biological functions. Recent experiments revealed several conflicting trends of the NRL dependence on the concentrations of histones and other architectural chromatin proteins, both in vitro and in vivo, but a systematic theoretical description of NRL as a function of DNA sequence and epigenetic determinants is currently lacking. To address this problem, we have performed an integrative biophysical and bioinformatics analysis in species ranging from yeast to frog to mouse where NRL was studied as a function of various parameters. We show that in simple eukaryotes such as yeast, a lower limit for the NRL value exists, determined by internucleosome interactions and remodeler action. For higher eukaryotes, also the upper limit exists since NRL is an increasing but saturating function of the linker histone concentration. Counterintuitively, smaller H1 variants or non-histone architectural proteins can initiate larger effects on the NRL due to entropic reasons. Furthermore, we demonstrate that different regimes of the NRL dependence on histone concentrations exist depending on whether DNA sequence-specific effects dominate over boundary effects or vice versa. We consider several classes of genomic regions with apparently different regimes of the NRL variation. As one extreme, our analysis reveals that the period of oscillations of the nucleosome density around bound RNA polymerase coincides with the period of oscillations of positioning sites of the corresponding DNA sequence. At another extreme, we show that although mouse major satellite repeats intrinsically encode well-defined nucleosome preferences, they have no unique nucleosome arrangement and can undergo a switch between two distinct types of nucleosome positioning.

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“…Using these set of phenomenological rates, we allow the system to evolve using the exact stochastic simulation method or the Gillespie kinetic Monte Carlo algorithm [20]. This algorithm has previously been used to model biological processes as diverse as gene regulation [33] and cytoskeletal filament growth [34]. In this approach, a set of 'N' rates is initiated for any given current configuration (set of coordinates of each particle and their valencies).…”

Section: Kinetic Monte Carlo Simulationsmentioning

confidence: 99%

Liquid-liquid microphase separation leads to formation of membraneless organelles

Ranganathan

Shakhnovich

2019

Preprint

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Proteins and nucleic acids can spontaneously self-assemble into membraneless droplet-like compartments, both in vitro and in vivo. A key component of these droplets are multi-valent proteins that possess several adhesive domains with specific interaction partners (whose number determines total valency of the protein) separated by disordered regions. Here, using multi-scale simulations we show that such proteins self-organize into micro-phase separated droplets of various sizes as opposed to the Flory-like macro-phase separated equilibrium state of homopolymers or equilibrium physical gels. We show that the micro-phase separated state is a dynamic outcome of the interplay between two competing processes: a diffusion-limited encounter between proteins, and the dynamics within small clusters that results in exhaustion of available valencies whereby all specifically interacting domains find their interacting partners within smaller clusters, leading to arrested phase separation. We first model these multi-valent chains as bead-spring polymers with multiple adhesive domains separated by semi-flexible linkers and use Langevin Dynamics (LD) to assess how key timescales depend on the molecular properties of associating polymers. Using the time-scales from LD simulations, we develop a coarse-grained kinetic model to study this phenomenon at longer times. Consistent with LD simulations, the macro-phase separated state was only observed at high concentrations and large interaction valencies. Further, in the regime where cluster sizes approach macro-phase separation, the condensed phase becomes dynamically solid-like, suggesting that it might no longer be biologically functional. Therefore, the micro-phase separated state could be a hallmark of functional droplets formed by proteins with the sticker-spacer architecture. Significance statementMembraneless organells (MO) are ubiquitous in 'healthy' living cells, with an altered state in disease. Their formation is likened to liquid-liquid phase separation (LLPS) between MO-forming proteins. However most models of LLPS predict complete macrophase separation while in reality MO's are small droplets of various sizes, which are malleable to rapid morphological changes. Here we present a microscopic multiscale theoretical study of thermodynamics and kinetics of formation of MO. We show that MO's are long-living dynamic structures formed as a result of arrested macrophase separation. Our study provides a direct link beween the molecular properies of MO-forming proteins and the morphology and dynamics of MO paving a path to rational design and control of MO.

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Nucleosome positioning and kinetics near transcription-start-site barriers are controlled by interplay between active remodeling and DNA sequence

Cited by 34 publications

References 44 publications

On the role of transcription in positioning nucleosomes

On the role of transcription in positioning nucleosomes

Regulation of the Nucleosome Repeat Length In Vivo by the DNA Sequence, Protein Concentrations and Long-Range Interactions

Liquid-liquid microphase separation leads to formation of membraneless organelles

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