Genomic DNA is folded into loops and topologically associating domains (TADs), which serve important structural and regulatory roles. It has been proposed that these genomic structures are formed by ...a loop extrusion process, which is mediated by structural maintenance of chromosomes (SMC) protein complexes. Recent single-molecule studies have shown that the SMC complexes condensin and cohesin are indeed able to extrude DNA into loops. In this Review, we discuss how the loop extrusion hypothesis can explain key features of genome architecture; cellular functions of loop extrusion, such as separation of replicated DNA molecules, facilitation of enhancer-promoter interactions and immunoglobulin gene recombination; and what is known about the mechanism of loop extrusion and its regulation, for example, by chromatin boundaries that depend on the DNA binding protein CTCF. We also discuss how the loop extrusion hypothesis has led to a paradigm shift in our understanding of both genome architecture and the functions of SMC complexes.
The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to ...catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. Recent discoveries have revealed an unexpected multitude of mechanisms that control APC/C activity, and have provided a first insight into how this unusual ubiquitin ligase recognizes its substrates.
Mammalian genomes are spatially organized into compartments, topologically associating domains (TADs), and loops to facilitate gene regulation and other chromosomal functions. How compartments, TADs, ...and loops are generated is unknown. It has been proposed that cohesin forms TADs and loops by extruding chromatin loops until it encounters CTCF, but direct evidence for this hypothesis is missing. Here, we show that cohesin suppresses compartments but is required for TADs and loops, that CTCF defines their boundaries, and that the cohesin unloading factor WAPL and its PDS5 binding partners control the length of loops. In the absence of WAPL and PDS5 proteins, cohesin forms extended loops, presumably by passing CTCF sites, accumulates in axial chromosomal positions (vermicelli), and condenses chromosomes. Unexpectedly, PDS5 proteins are also required for boundary function. These results show that cohesin has an essential genome‐wide function in mediating long‐range chromatin interactions and support the hypothesis that cohesin creates these by loop extrusion, until it is delayed by CTCF in a manner dependent on PDS5 proteins, or until it is released from DNA by WAPL.
Synopsis
Spatial organization of mammalian genomes facilitates gene regulation and replication. Hi‐C data reveal that cohesin binding at CTCF sites controls long‐range chromatin interactions, supporting a model in which chromatin loop extrusion drives genome 3D architecture.
Cohesin suppresses compartments but is required for TADs and loops.
CTCF and PDS5 proteins define TAD boundaries and loop anchors.
WAPL and PDS5 proteins define the length of loops.
Cohesin appears to form long‐range contacts by loop extrusion.
Hi‐C data show that cohesin is required for long‐range chromatin interactions, supporting a model of loop extrusion driving the spatial organization of mammalian genomes.
DNA loop extrusion by human cohesin Davidson, Iain F; Bauer, Benedikt; Goetz, Daniela ...
Science (American Association for the Advancement of Science),
12/2019, Letnik:
366, Številka:
6471
Journal Article
Recenzirano
Odprti dostop
Eukaryotic genomes are folded into loops and topologically associating domains, which contribute to chromatin structure, gene regulation, and gene recombination. These structures depend on cohesin, a ...ring-shaped DNA-entrapping adenosine triphosphatase (ATPase) complex that has been proposed to form loops by extrusion. Such an activity has been observed for condensin, which forms loops in mitosis, but not for cohesin. Using biochemical reconstitution, we found that single human cohesin complexes form DNA loops symmetrically at rates up to 2.1 kilo-base pairs per second. Loop formation and maintenance depend on cohesin's ATPase activity and on NIPBL-MAU2, but not on topological entrapment of DNA by cohesin. During loop formation, cohesin and NIPBL-MAU2 reside at the base of loops, which indicates that they generate loops by extrusion. Our results show that cohesin and NIPBL-MAU2 form an active holoenzyme that interacts with DNA either pseudo-topologically or non-topologically to extrude genomic interphase DNA into loops.
Humans discount the value of future rewards over time. Here we show using functional magnetic resonance imaging (fMRI) and neural coupling analyses that episodic future thinking reduces the rate of ...delay discounting through a modulation of neural decision-making and episodic future thinking networks. In addition to a standard control condition, real subject-specific episodic event cues were presented during a delay discounting task. Spontaneous episodic imagery during cue processing predicted how much subjects changed their preferences toward more future-minded choice behavior. Neural valuation signals in the anterior cingulate cortex and functional coupling of this region with hippocampus and amygdala predicted the degree to which future thinking modulated individual preference functions. A second experiment replicated the behavioral effects and ruled out alternative explanations such as date-based processing and temporal focus. The present data reveal a mechanism through which neural decision-making and prospection networks can interact to generate future-minded choice behavior.
► Episodic imagery reduces impulsivity in intertemporal decision-making ► Adjustments in discounting were predicted by the degree of ACC-hippocampal coupling ► Decision-making and prospection networks interact to enable future-minded choice
Humans and animals prefer immediate over delayed rewards (delay discounting). This preference for smaller-but-sooner over larger-but-later rewards shows substantial interindividual variability in ...healthy subjects. Moreover, a strong bias towards immediate reinforcement characterizes many psychiatric conditions such as addiction and attention-deficit hyperactivity disorder. We discuss the neural mechanisms underlying delay discounting and describe how interindividual variability (trait effects) in the neural instantiation of subprocesses of delay discounting (such as reward valuation, cognitive control and prospection) contributes to differences in behaviour. We next discuss different interventions that can partially remedy impulsive decision-making (state effects). Although the precise neural mechanisms underlying many of these modulating influences are only beginning to be unravelled, they point towards novel treatment approaches for disorders of impulse control.
‘Structural maintenance of chromosomes’ (SMC) complexes are required for the folding of genomic DNA into loops. Theoretical considerations and single-molecule experiments performed with the SMC ...complexes cohesin and condensin indicate that DNA folding occurs via loop extrusion. Recent work indicates that this process is essential for the assembly of antigen receptor genes by V(D)J recombination in developing B and T cells of the vertebrate immune system. Here, I review how recent studies of the mouse immunoglobulin heavy chain locus Igh have provided evidence for this hypothesis and how the formation of chromatin loops by cohesin and regulation of this process by CTCF and Wapl might ensure that all variable gene segments in this locus (VH segments) participate in recombination with a re-arranged DJH segment, to ensure generation of a maximally diverse repertoire of B-cell receptors and antibodies.
•Aging decreases sensitivity for pain of low intensity.•Reduced sensitivity is especially apparent for heat pain and for pain applied to the head.•Age-related increases in pain thresholds are ...greatest the wider the age gap between groups.•Aging has no strong effect on pain tolerance.
Demographic changes, with substantial increase in life expectancy, ask for solid knowledge about how pain perception might be altered by aging. Although psychophysical studies on age-related changes in pain perception have been conducted over more than 70 years, meta-analyses are still missing. The present meta-analysis aimed to quantify evidence on age-related changes in pain perception, indexed by pain thresholds and pain tolerance thresholds in young and older healthy adults. After searching PubMed, Google Scholar and PsycINFO using state-of-art screening (PRISMA-criteria), 31 studies on pain threshold and 9 studies assessing pain tolerance threshold were identified. Pain threshold increases with age, which is indicated by a large effect size. This age-related change increases the wider the age-gap between groups; and is especially prominent when heat is used and when stimuli are applied to the head. In contrast, pain tolerance thresholds did not show substantial age-related changes. Thus, after many years of investigating age-related changes in pain perception, we only have firm evidence that aging reduces pain sensitivity for lower pain intensities.
Reinforcement learning in robotics: A survey Kober, Jens; Bagnell, J. Andrew; Peters, Jan
The International journal of robotics research,
09/2013, Letnik:
32, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Reinforcement learning offers to robotics a framework and set of tools for the design of sophisticated and hard-to-engineer behaviors. Conversely, the challenges of robotic problems provide both ...inspiration, impact, and validation for developments in reinforcement learning. The relationship between disciplines has sufficient promise to be likened to that between physics and mathematics. In this article, we attempt to strengthen the links between the two research communities by providing a survey of work in reinforcement learning for behavior generation in robots. We highlight both key challenges in robot reinforcement learning as well as notable successes. We discuss how contributions tamed the complexity of the domain and study the role of algorithms, representations, and prior knowledge in achieving these successes. As a result, a particular focus of our paper lies on the choice between model-based and model-free as well as between value-function-based and policy-search methods. By analyzing a simple problem in some detail we demonstrate how reinforcement learning approaches may be profitably applied, and we note throughout open questions and the tremendous potential for future research.
Fertilization triggers assembly of higher‐order chromatin structure from a condensed maternal and a naïve paternal genome to generate a totipotent embryo. Chromatin loops and domains have been ...detected in mouse zygotes by single‐nucleus Hi‐C (snHi‐C), but not bulk Hi‐C. It is therefore unclear when and how embryonic chromatin conformations are assembled. Here, we investigated whether a mechanism of cohesin‐dependent loop extrusion generates higher‐order chromatin structures within the one‐cell embryo. Using snHi‐C of mouse knockout embryos, we demonstrate that the zygotic genome folds into loops and domains that critically depend on Scc1‐cohesin and that are regulated in size and linear density by Wapl. Remarkably, we discovered distinct effects on maternal and paternal chromatin loop sizes, likely reflecting differences in loop extrusion dynamics and epigenetic reprogramming. Dynamic polymer models of chromosomes reproduce changes in snHi‐C, suggesting a mechanism where cohesin locally compacts chromatin by active loop extrusion, whose processivity is controlled by Wapl. Our simulations and experimental data provide evidence that cohesin‐dependent loop extrusion organizes mammalian genomes over multiple scales from the one‐cell embryo onward.
Synopsis
Zygotic genomes fold into loops and domains that depend on cohesin and are regulated in size by Wapl. Single‐nucleus Hi‐C and polymer models of chromosomes provide evidence for cohesin‐dependent loop extrusion organizing genomes over multiple scales.
Zygotic genomes are organized into cohesin‐dependent chromatin loops and Topologically Associating Domains (TADs).
Loop extrusion leads to different loop strengths in maternal and paternal genomes.
Cohesin restricts inter‐chromosomal interactions by altering chromosome surface area.
Loop extrusion organizes chromatin at multiple genomic scales.
Single‐nucleus Hi‐C and microscopy show that the zygotic genome folds into loops and domains in a cohesin‐dependent manner with differences in maternal and paternal chromosome organization.
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