85 research outputs found
A nonequilibrium strategy for fast target search on the genome
Vital biological processes such as genome repair require fast and efficient
binding of selected proteins to specific target sites on DNA. Here we propose
an active target search mechanism based on "chromophoresis", the dynamics of
DNA-binding proteins up or down gradients in the density of epigenetic marks,
or colours (biochemical tags on the genome). We focus on a set of proteins that
deposit marks from which they are repelled---a case which is only encountered
away from thermodynamic equilibrium. For suitable ranges of kinetic parameter
values, chromophoretic proteins can perform unidirectional motion and are
optimally redistributed along the genome. Importantly, they can also locally
unravel a region of the genome which is collapsed due to self-interactions and
"dive" deep into its core, for a striking enhancement of the efficiency of
target search on such an inaccessible substrate. We discuss the potential
relevance of chromophoresis for the location of DNA lesions.Comment: 5 pages, 5 figure
Chromosome compaction and chromatin stiffness enhance diffusive loop extrusion by slip-link proteins
We use Brownian dynamics simulations to study the formation of chromatin
loops through diffusive sliding of slip-link-like proteins, mimicking the
behaviour of cohesin molecules. We recently proposed that diffusive sliding is
sufficient to explain the extrusion of chromatin loops of hundreds of
kilo-base-pairs (kbp), which may then be stabilised by interactions between
cohesin and CTCF proteins. Here we show that the flexibility of the chromatin
fibre strongly affects this dynamical process, and find that diffusive loop
extrusion is more efficient on stiffer chromatin regions. We also show that the
dynamics of loop formation are faster in confined and collapsed chromatin
conformations but that this enhancement is counteracted by the increased
crowding. We provide a simple theoretical argument explaining why stiffness and
collapsed conformations favour diffusive extrusion. In light of the
heterogeneous physical and conformational properties of eukaryotic chromatin,
we suggest that our results are relevant to understand the looping and
organisation of interphase chromosomes in vivo
Integrating transposable elements in the 3D genome
Chromosome organisation is increasingly recognised as an essential component of genome regulation, cell fate and cell health. Within the realm of transposable elements (TEs) however, the spatial information of how genomes are folded is still only rarely integrated in experimental studies or accounted for in modelling. Whilst polymer physics is recognised as an important tool to understand the mechanisms of genome folding, in this commentary we discuss its potential applicability to aspects of TE biology. Based on recent works on the relationship between genome organisation and TE integration, we argue that existing polymer models may be extended to create a predictive framework for the study of TE integration patterns. We suggest that these models may offer orthogonal and generic insights into the integration profiles (or "topography") of TEs across organisms. In addition, we provide simple polymer physics arguments and preliminary molecular dynamics simulations of TEs inserting into heterogeneously flexible polymers. By considering this simple model, we show how polymer folding and local flexibility may generically affect TE integration patterns. The preliminary discussion reported in this commentary is aimed to lay the foundations for a large-scale analysis of TE integration dynamics and topography as a function of the three-dimensional host genome
Dynamical Scaling and Phase Coexistence in Topologically-Constrained DNA Melting
There is a long-standing experimental observation that the melting of
topologically constrained DNA, such as circular-closed plasmids, is less abrupt
than that of linear molecules. This finding points to an intriguing role of
topology in the physics of DNA denaturation, which is however poorly
understood. Here, we shed light on this issue by combining large-scale Brownian
Dynamics simulations with an analytically solvable phenomenological Landau mean
field theory. We find that the competition between melting and supercoiling
leads to phase coexistence of denatured and intact phases at the single
molecule level. This coexistence occurs in a wide temperature range, thereby
accounting for the broadening of the transition. Finally, our simulations show
an intriguing topology-dependent scaling law governing the growth of
denaturation bubbles in supercoiled plasmids, which can be understood within
the proposed mean field theory.Comment: main text + S
Bridging-induced phase separation induced by cohesin SMC protein complexes
Structural maintenance of chromosome (SMC) protein complexes are able to extrude DNA loops. While loop extrusion constitutes a fundamental building block of chromosomes, other factors may be equally important. Here, we show that yeast cohesin exhibits pronounced clustering on DNA, with all the hallmarks of biomolecular condensation. DNA-cohesin clusters exhibit liquid-like behavior, showing fusion of clusters, rapid fluorescence recovery after photobleaching and exchange of cohesin with the environment. Strikingly, the in vitro clustering is DNA length dependent, as cohesin forms clusters only on DNA exceeding 3 kilo-base pairs. We discuss how bridging-induced phase separation, a previously unobserved type of biological condensation, can explain the DNA-cohesin clustering through DNA-cohesin-DNA bridges. We confirm that, in yeast cells in vivo, a fraction of cohesin associates with chromatin in a manner consistent with bridging-induced phase separation. Biomolecular condensation by SMC proteins constitutes a new basic principle by which SMC complexes direct genome organization.BN/Cees Dekker LabQN/Afdelingsburea
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