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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.Chromatin loops are proposed to be formed through loop extrusion by structural maintenance of chromosomes (SMC) complexes. Recent studies have shown that the SMC complexes condensin and cohesin are indeed able to extrude DNA, and caused a paradigm shift in our understanding of genome organization and the cellular functions of SMC complexes.

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.

Key Points The anaphase promoting complex/cyclosome (APC/C) is a 1.5-MDa ubiquitin ligase complex that initiates sister-chromatid separation and exit from mitosis by targeting cyclin B and securin for destruction by the 26S proteasome. APC/C activity is also indirectly required for DNA replication, because APC/C-mediated cyclin degradation leads to the inactivation of cyclin-dependent kinase-1 (Cdk1), which is a prerequisite for the assembly of pre-replication complexes. APC/C is activated by proteins of the Cdc20/Cdh1 family. The interaction between APC/C and its co-activators is tightly controlled by phosphorylation and is restricted to mitosis and G1 phase. In addition, APC/C activity can be restrained by a number of inhibitory proteins. Mad2 and BubR1 inhibit APC/C during spindle assembly and thereby prevent precocious initiation of anaphase and exit from mitosis. Members of the early mitotic inhibitor-1 (EMI1)/regulator of cyclin A-1 (RCA1) family inhibit APC/C from S phase until early mitosis and during meiosis in vertebrate eggs. Co-activator proteins activate APC/C by facilitating the recruitment of substrates. All known APC/C co-activators contain a propeller-shaped WD40 domain that interacts with a recognition element in APC/C substrates and is known as the destruction box (D-box). Co-activators are required but not sufficient for substrate recognition because the APC/C subunit Doc1 is also needed for this process. Several observations suggest that the D-box of substrates might interact with both co-activators and APC/C subunits to form a ternary complex in which substrate ubiquitylation occurs. The anaphase promoting complex/cyclosome (APC/C) is the largest known complex that catalyses ubiquitylation reactions and has key functions in the eukaryotic cell cycle. Recent studies have shed light on how APC/C activity is controlled and how it recognizes a multitude of substrates. 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.

In eukaryotes, genomic DNA is extruded into loops by cohesin 1 . By restraining this process, the DNA-binding protein CCCTC-binding factor (CTCF) generates topologically associating domains (TADs) 2 , 3 that have important roles in gene regulation and recombination during development and disease 1 , 4 – 7 . How CTCF establishes TAD boundaries and to what extent these are permeable to cohesin is unclear 8 . Here, to address these questions, we visualize interactions of single CTCF and cohesin molecules on DNA in vitro. We show that CTCF is sufficient to block diffusing cohesin, possibly reflecting how cohesive cohesin accumulates at TAD boundaries, and is also sufficient to block loop-extruding cohesin, reflecting how CTCF establishes TAD boundaries. CTCF functions asymmetrically, as predicted; however, CTCF is dependent on DNA tension. Moreover, CTCF regulates cohesin’s loop-extrusion activity by changing its direction and by inducing loop shrinkage. Our data indicate that CTCF is not, as previously assumed, simply a barrier to cohesin-mediated loop extrusion but is an active regulator of this process, whereby the permeability of TAD boundaries can be modulated by DNA tension. These results reveal mechanistic principles of how CTCF controls loop extrusion and genome architecture. CTCF is sufficient to block loop extruding cohesin in a DNA tension dependent manner, and induces loop extrusion direction switching and loop shrinkage.

Many motor skills in humanoid robotics can be learned using parametrized motor primitives. While successful applications to date have been achieved with imitation learning, most of the interesting motor learning problems are high-dimensional reinforcement learning problems. These problems are often beyond the reach of current reinforcement learning methods. In this paper, we study parametrized policy search methods and apply these to benchmark problems of motor primitive learning in robotics. We show that many well-known parametrized policy search methods can be derived from a general, common framework. This framework yields both policy gradient methods and expectation-maximization (EM) inspired algorithms. We introduce a novel EM-inspired algorithm for policy learning that is particularly well-suited for dynamical system motor primitives. We compare this algorithm, both in simulation and on a real robot, to several well-known parametrized policy search methods such as episodic REINFORCE, ‘Vanilla’ Policy Gradients with optimal baselines, episodic Natural Actor Critic, and episodic Reward-Weighted Regression. We show that the proposed method out-performs them on an empirical benchmark of learning dynamical system motor primitives both in simulation and on a real robot. We apply it in the context of motor learning and show that it can learn a complex Ball-in-a-Cup task on a real Barrett WAM™ robot arm.

The distribution of cohesin in the mouse genome depends on CTCF, transcription and the cohesin release factor Wapl. Cohesin distribution in mammalian genome Cohesin and CTCF are known to spatially organize mammalian genomes into chromatin loops and topologically associated domains. CTCF binds to specific DNA sequences, but it is unclear how cohesin is recruited to these sites. Here, Jan-Michael Peters and colleagues show that the distribution of cohesin in the mouse genome depends on CTCF, transcription and the cohesin-release factor Wapl. In the absence of CTCF, cohesin accumulates at the transcription start sites of active genes, which are bound by the cohesion-loading complex. In the absence of both CTCF and Wapl, cohesin accumulates at the 3′ end of active genes. The authors propose that cohesin is loaded onto DNA at sites that are distinct from its final binding sites and can be translocated by transcription until it either encounters CTCF bound to DNA or is released by Wapl. A mechanism of transcription-mediated cohesin translocation could allow the extrusion of chromatin loops. Mammalian genomes are spatially organized by CCCTC-binding factor (CTCF) and cohesin into chromatin loops 1 , 2 and topologically associated domains 3 , 4 , 5 , 6 , which have important roles in gene regulation 1 , 2 , 4 , 5 , 7 and recombination 7 , 8 , 9 . By binding to specific sequences 10 , CTCF defines contact points for cohesin-mediated long-range chromosomal cis -interactions 1 , 2 , 4 , 5 , 6 , 7 , 11 . Cohesin is also present at these sites 12 , 13 , but has been proposed to be loaded onto DNA elsewhere 14 , 15 and to extrude chromatin loops until it encounters CTCF bound to DNA 16 , 17 , 18 , 19 . How cohesin is recruited to CTCF sites, according to this or other models, is unknown. Here we show that the distribution of cohesin in the mouse genome depends on transcription, CTCF and the cohesin release factor Wings apart-like (Wapl). In CTCF-depleted fibroblasts, cohesin cannot be properly recruited to CTCF sites but instead accumulates at transcription start sites of active genes, where the cohesin-loading complex is located 14 , 15 . In the absence of both CTCF and Wapl, cohesin accumulates in up to 70 kilobase-long regions at 3′-ends of active genes, in particular if these converge on each other. Changing gene expression modulates the position of these ‘cohesin islands’. These findings indicate that transcription can relocate mammalian cohesin over long distances on DNA, as previously reported for yeast cohesin 20 , 21 , 22 , 23 , that this translocation contributes to positioning cohesin at CTCF sites, and that active genes can be freed from cohesin either by transcription-mediated translocation or by Wapl-mediated release.

Sequential sampling models such as the drift diffusion model (DDM) have a long tradition in research on perceptual decision-making, but mounting evidence suggests that these models can account for response time (RT) distributions that arise during reinforcement learning and value-based decision-making. Building on this previous work, we implemented the DDM as the choice rule in inter-temporal choice (temporal discounting) and risky choice (probability discounting) using hierarchical Bayesian parameter estimation. We validated our approach in data from nine patients with focal lesions to the ventromedial prefrontal cortex / medial orbitofrontal cortex (vmPFC/mOFC) and nineteen age- and education-matched controls. Model comparison revealed that, for both tasks, the data were best accounted for by a variant of the drift diffusion model including a non-linear mapping from value-differences to trial-wise drift rates. Posterior predictive checks confirmed that this model provided a superior account of the relationship between value and RT. We then applied this modeling framework and 1) reproduced our previous results regarding temporal discounting in vmPFC/mOFC patients and 2) showed in a previously unpublished data set on risky choice that vmPFC/mOFC patients exhibit increased risk-taking relative to controls. Analyses of DDM parameters revealed that patients showed substantially increased non-decision times and reduced response caution during risky choice. In contrast, vmPFC/mOFC damage abolished neither scaling nor asymptote of the drift rate. Relatively intact value processing was also confirmed using DDM mixture models, which revealed that in both groups >98% of trials were better accounted for by a DDM with value modulation than by a null model without value modulation. Our results highlight that novel insights can be gained from applying sequential sampling models in studies of inter-temporal and risky decision-making in cognitive neuroscience.

Cohesin complexes mediate sister chromatid cohesion. Cohesin also becomes enriched at DNA double‐strand break sites and facilitates recombinational DNA repair. Here, we report that cohesin is essential for the DNA damage‐induced G2/M checkpoint. In contrast to cohesin's role in DNA repair, the checkpoint function of cohesin is independent of its ability to mediate cohesion. After RNAi‐mediated depletion of cohesin, cells fail to properly activate the checkpoint kinase Chk2 and have defects in recruiting the mediator protein 53BP1 to DNA damage sites. Earlier work has shown that phosphorylation of the cohesin subunits Smc1 and Smc3 is required for the intra‐S checkpoint, but Smc1/Smc3 are also subunits of a distinct recombination complex, RC‐1. It was, therefore, unknown whether Smc1/Smc3 function in the intra‐S checkpoint as part of cohesin. We show that Smc1/Smc3 are phosphorylated as part of cohesin and that cohesin is required for the intra‐S checkpoint. We propose that accumulation of cohesin at DNA break sites is not only needed to mediate DNA repair, but also facilitates the recruitment of checkpoint proteins, which activate the intra‐S and G2/M checkpoints.

Nuclear processes, such as V(D)J recombination, are orchestrated by the three-dimensional organization of chromosomes at multiple levels, including compartments 1 and topologically associated domains (TADs) 2 , 3 consisting of chromatin loops 4 . TADs are formed by chromatin-loop extrusion 5 – 7 , which depends on the loop-extrusion function of the ring-shaped cohesin complex 8 – 12 . Conversely, the cohesin-release factor Wapl 13 , 14 restricts loop extension 10 , 15 . The generation of a diverse antibody repertoire, providing humoral immunity to pathogens, requires the participation of all V genes in V(D)J recombination 16 , which depends on contraction of the 2.8-Mb-long immunoglobulin heavy chain ( Igh ) locus by Pax5 17 , 18 . However, how Pax5 controls Igh contraction in pro-B cells remains unknown. Here we demonstrate that locus contraction is caused by loop extrusion across the entire Igh locus. Notably, the expression of Wapl is repressed by Pax5 specifically in pro-B and pre-B cells, facilitating extended loop extrusion by increasing the residence time of cohesin on chromatin. Pax5 mediates the transcriptional repression of Wapl through a single Pax5-binding site by recruiting the polycomb repressive complex 2 to induce bivalent chromatin at the Wapl promoter. Reduced Wapl expression causes global alterations in the chromosome architecture, indicating that the potential to recombine all V genes entails structural changes of the entire genome in pro-B cells. Pax5 regulates contraction of the immunoglobulin heavy chain ( Igh ) locus—an essential step in V(D)J recombination—by promoting chromatin loop extrusion via repression of Wapl expression.