Novel technologies revealed a nontrivial spatial organization of the chromosomes within the cell nucleus, which includes different levels of compartmentalization and architectural patterns. Notably, ...such complex three-dimensional structure plays a crucial role in vital biological functions and its alterations can produce extensive rewiring of genomic regulatory regions, thus leading to gene misexpression and disease. Here, we show that theoretical and computational approaches, based on polymer physics, can be employed to dissect chromatin contacts in three-dimensional space and to predict the effects of pathogenic structural variants on the genome architecture. In particular, we discuss the folding of the human EPHA4 and the murine Pitx1 loci as case studies.
By detailed molecular dynamics and Monte Carlo simulations of a model system we show that granular materials at rest can be described as thermodynamics systems. First, we show that granular packs can ...be characterized by few parameters, as much as fluids or solids. Then, in a second independent step, we demonstrate that these states can be described in terms of equilibrium distributions which coincide with the statistical mechanics of powders first proposed by Edwards. We also derive the system equation of state as a function of the "configurational temperature," its new intensive thermodynamic parameter.
Some biological questions are tough to solve through standard molecular and cell biological methods and naturally lend themselves to investigation by physical approaches. Below, a group of formally ...trained physicists discuss, among other things, how they apply physics to address biological questions and how physical approaches complement conventional biological approaches.
We review the picture emerging from recently published models of classical polymer physics of the general features of chromatin large scale spatial organization, as revealed by microscopy and Hi-C ...data.
Differentiation of lymphocytes is frequently accompanied by cell cycle changes, interplay that is of central importance for immunity but is still incompletely understood. Here, we interrogate and ...quantitatively model how proliferation is linked to differentiation in CD4+ T cells.
We perform ex vivo single-cell RNA-sequencing of CD4+ T cells during a mouse model of infection that elicits a type 2 immune response and infer that the differentiated, cytokine-producing cells cycle faster than early activated precursor cells. To dissect this phenomenon quantitatively, we determine expression profiles across consecutive generations of differentiated and undifferentiated cells during Th2 polarization in vitro. We predict three discrete cell states, which we verify by single-cell quantitative PCR. Based on these three states, we extract rates of death, division and differentiation with a branching state Markov model to describe the cell population dynamics. From this multi-scale modelling, we infer a significant acceleration in proliferation from the intermediate activated cell state to the mature cytokine-secreting effector state. We confirm this acceleration both by live imaging of single Th2 cells and in an ex vivo Th1 malaria model by single-cell RNA-sequencing.
The link between cytokine secretion and proliferation rate holds both in Th1 and Th2 cells in vivo and in vitro, indicating that this is likely a general phenomenon in adaptive immunity.
We review the picture emerging from recently published models of classical polymer physics of the general features of chromatin large scale spatial organization, as revealed by microscopy and Hi-C ...data.
Polycomb repression in mouse embryonic stem cells (ESCs) is tightly associated with promoter co‐occupancy of RNA polymerase II (RNAPII) which is thought to prime genes for activation during early ...development. However, it is unknown whether RNAPII poising is a general feature of Polycomb repression, or is lost during differentiation. Here, we map the genome‐wide occupancy of RNAPII and Polycomb from pluripotent ESCs to non‐dividing functional dopaminergic neurons. We find that poised RNAPII complexes are ubiquitously present at Polycomb‐repressed genes at all stages of neuronal differentiation. We observe both loss and acquisition of RNAPII and Polycomb at specific groups of genes reflecting their silencing or activation. Strikingly, RNAPII remains poised at transcription factor genes which are silenced in neurons through Polycomb repression, and have major roles in specifying other, non‐neuronal lineages. We conclude that RNAPII poising is intrinsically associated with Polycomb repression throughout differentiation. Our work suggests that the tight interplay between RNAPII poising and Polycomb repression not only instructs promoter state transitions, but also may enable promoter plasticity in differentiated cells.
Synopsis
Poised RNAPII‐S5p is present at Polycomb‐repressed genes from embryonic stem cells to terminally differentiated neurons. The tight interplay between RNAPII poising and Polycomb repression enables promoter plasticity in differentiated cells and increased potential for reactivation.
Poised RNAPII‐S5p primes Polycomb‐repressed promoters throughout terminal differentiation to functional dopaminergic neurons.
Poised RNAPII‐S5p associates with increased potential for reactivation upon loss of Polycomb repression.
DNA methylation valleys coincide with broad occupancy of poised RNAPII‐S5p and Polycomb repression.
Key non‐neuronal transcription factor genes that co‐associate with Polycomb and RNAPII‐S5p in neurons have potential roles in transdifferentiation.
Poised RNAPII‐S5p is present at Polycomb‐repressed genes from embryonic stem cells to terminally differentiated neurons. The tight interplay between RNAPII poising and Polycomb repression enables promoter plasticity in differentiated cells and increased potential for reactivation.
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