Biophysical regulation of local chromatin structure

Gilbert, Nick

doi:10.1016/j.gde.2019.06.001

Cited by 14 publications

(11 citation statements)

References 76 publications

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“…Recent whole-genome sequencingbased studies have indeed revealed the depletion of nucleosomes at many promoter and enhancer regions to accommodate transcription (9,10). In addition, nucleosome positioning may affect gene expression indirectly by regulating higher-order chromatin organization (11)(12)(13)(14). For example, protein molecules such as Cohesin and CTCF have been shown to facilitate chromatin folding and the formation of socalled topologically associated domains (15,16).…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

On the role of transcription in positioning nucleosomes

Jiang

Zhang

2020

Preprint

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“…In higher eukaryotes, DNA is packaged into chromatin that is organized as chromosomes in the nucleus (Gilbert 2019). The organization and regulation of chromatin architecture has been studied for many years, because chromatin structure plays an important role in gene expression and genome integrity.…”

Section: A New View Of Chromatin Behaviormentioning

confidence: 99%

Biological phase separation: cell biology meets biophysics

et al. 2020

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Progress in development of biophysical analytic approaches has recently crossed paths with macromolecule condensates in cells. These cell condensates, typically termed liquid-like droplets, are formed by liquid-liquid phase separation (LLPS). More and more cell biologists now recognize that many of the membrane-less organelles observed in cells are formed by LLPS caused by interactions between proteins and nucleic acids. However, the detailed biophysical processes within the cell that lead to these assemblies remain largely unexplored. In this review, we evaluate recent discoveries related to biological phase separation including stress granule formation, chromatin regulation, and processes in the origin and evolution of life. We also discuss the potential issues and technical advancements required to properly study biological phase separation.

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“…This remains an interesting topic, firstly, because, inside the densely populated chromatin space of the nucleoplasm, the kinetics of topoisomerase-binding to waves of (+) supercoiling are not well understood. Second, the conformations that a transiently (+) supercoiled chromatin fiber generated by a translocating replisome may adopt remain elusive [ 51 ]. Third, topoisomerase action always requires DNA strand breakage, which must occur either at some distance ahead of an approaching replisome in order to avoid catastrophic collisions, or demands replisome pausing during topoisomerase action.…”

Section: Established Solutions At Topologically Stressed Replicatimentioning

confidence: 99%

“…TOP1B finds its substrate in the form of double-stranded DNA crossings [ 56 ], which is a key feature of plectonemic supercoiled DNA [ 23 ]. However, whether transiently (+) supercoiled chromatin fibers adopt a similar interwound structure has not been established [ 51 ]. In any case, diffusion-controlled search modes would imply that a certain level of recognizable (+) chromatin supercoiling must have been generated by a replisome.…”

Section: Established Solutions At Topologically Stressed Replicatimentioning

confidence: 99%

Chromatin Architectural Factors as Safeguards against Excessive Supercoiling during DNA Replication

Ahmed

Dröge

2020

IJMS

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Key DNA transactions, such as genome replication and transcription, rely on the speedy translocation of specialized protein complexes along a double-stranded, right-handed helical template. Physical tethering of these molecular machines during translocation, in conjunction with their internal architectural features, generates DNA topological strain in the form of template supercoiling. It is known that the build-up of transient excessive supercoiling poses severe threats to genome function and stability and that highly specialized enzymes—the topoisomerases (TOP)—have evolved to mitigate these threats. Furthermore, due to their intracellular abundance and fast supercoil relaxation rates, it is generally assumed that these enzymes are sufficient in coping with genome-wide bursts of excessive supercoiling. However, the recent discoveries of chromatin architectural factors that play important accessory functions have cast reasonable doubts on this concept. Here, we reviewed the background of these new findings and described emerging models of how these accessory factors contribute to supercoil homeostasis. We focused on DNA replication and the generation of positive (+) supercoiling in front of replisomes, where two accessory factors—GapR and HMGA2—from pro- and eukaryotic cells, respectively, appear to play important roles as sinks for excessive (+) supercoiling by employing a combination of supercoil constrainment and activation of topoisomerases. Looking forward, we expect that additional factors will be identified in the future as part of an expanding cellular repertoire to cope with bursts of topological strain. Furthermore, identifying antagonists that target these accessory factors and work synergistically with clinically relevant topoisomerase inhibitors could become an interesting novel strategy, leading to improved treatment outcomes.

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Biophysical regulation of local chromatin structure

Cited by 14 publications

References 76 publications

On the role of transcription in positioning nucleosomes

On the role of transcription in positioning nucleosomes

Biological phase separation: cell biology meets biophysics

Chromatin Architectural Factors as Safeguards against Excessive Supercoiling during DNA Replication

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