@article{12188, abstract = {Molecular mechanisms enabling the switching and maintenance of epigenetic states are not fully understood. Distinct histone modifications are often associated with ON/OFF epigenetic states, but how these states are stably maintained through DNA replication, yet in certain situations switch from one to another remains unclear. Here, we address this problem through identification of Arabidopsis INCURVATA11 (ICU11) as a Polycomb Repressive Complex 2 accessory protein. ICU11 robustly immunoprecipitated in vivo with PRC2 core components and the accessory proteins, EMBRYONIC FLOWER 1 (EMF1), LIKE HETEROCHROMATIN PROTEIN1 (LHP1), and TELOMERE_REPEAT_BINDING FACTORS (TRBs). ICU11 encodes a 2-oxoglutarate-dependent dioxygenase, an activity associated with histone demethylation in other organisms, and mutant plants show defects in multiple aspects of the Arabidopsis epigenome. To investigate its primary molecular function we identified the Arabidopsis FLOWERING LOCUS C (FLC) as a direct target and found icu11 disrupted the cold-induced, Polycomb-mediated silencing underlying vernalization. icu11 prevented reduction in H3K36me3 levels normally seen during the early cold phase, supporting a role for ICU11 in H3K36me3 demethylation. This was coincident with an attenuation of H3K27me3 at the internal nucleation site in FLC, and reduction in H3K27me3 levels across the body of the gene after plants were returned to the warm. Thus, ICU11 is required for the cold-induced epigenetic switching between the mutually exclusive chromatin states at FLC, from the active H3K36me3 state to the silenced H3K27me3 state. These data support the importance of physical coupling of histone modification activities to promote epigenetic switching between opposing chromatin states.}, author = {Bloomer, Rebecca H. and Hutchison, Claire E. and Bäurle, Isabel and Walker, James and Fang, Xiaofeng and Perera, Pumi and Velanis, Christos N. and Gümüs, Serin and Spanos, Christos and Rappsilber, Juri and Feng, Xiaoqi and Goodrich, Justin and Dean, Caroline}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, keywords = {Multidisciplinary}, number = {28}, pages = {16660--16666}, publisher = {Proceedings of the National Academy of Sciences}, title = {{The Arabidopsis epigenetic regulator ICU11 as an accessory protein of polycomb repressive complex 2}}, doi = {10.1073/pnas.1920621117}, volume = {117}, year = {2020}, } @article{7724, abstract = {Modern molecular genetic datasets, primarily collected to study the biology of human health and disease, can be used to directly measure the action of natural selection and reveal important features of contemporary human evolution. Here we leverage the UK Biobank data to test for the presence of linear and nonlinear natural selection in a contemporary population of the United Kingdom. We obtain phenotypic and genetic evidence consistent with the action of linear/directional selection. Phenotypic evidence suggests that stabilizing selection, which acts to reduce variance in the population without necessarily modifying the population mean, is widespread and relatively weak in comparison with estimates from other species.}, author = {Sanjak, Jaleal S. and Sidorenko, Julia and Robinson, Matthew Richard and Thornton, Kevin R. and Visscher, Peter M.}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, number = {1}, pages = {151--156}, publisher = {Proceedings of the National Academy of Sciences}, title = {{Evidence of directional and stabilizing selection in contemporary humans}}, doi = {10.1073/pnas.1707227114}, volume = {115}, year = {2018}, } @article{6109, abstract = {Neuropeptides are ubiquitous modulators of behavior and physiology. They are packaged in specialized secretory organelles called dense core vesicles (DCVs) that are released upon neural stimulation. Unlike synaptic vesicles, which can be recycled and refilled close to release sites, DCVs must be replenished by de novo synthesis in the cell body. Here, we dissect DCV cell biology in vivo in a Caenorhabditis elegans sensory neuron whose tonic activity we can control using a natural stimulus. We express fluorescently tagged neuropeptides in the neuron and define parameters that describe their subcellular distribution. We measure these parameters at high and low neural activity in 187 mutants defective in proteins implicated in membrane traffic, neuroendocrine secretion, and neuronal or synaptic activity. Using unsupervised hierarchical clustering methods, we analyze these data and identify 62 groups of genes with similar mutant phenotypes. We explore the function of a subset of these groups. We recapitulate many previous findings, validating our paradigm. We uncover a large battery of proteins involved in recycling DCV membrane proteins, something hitherto poorly explored. We show that the unfolded protein response promotes DCV production, which may contribute to intertissue communication of stress. We also find evidence that different mechanisms of priming and exocytosis may operate at high and low neural activity. Our work provides a defined framework to study DCV biology at different neural activity levels.}, author = {Laurent, Patrick and Ch’ng, QueeLim and Jospin, Maëlle and Chen, Changchun and Lorenzo, Ramiro and de Bono, Mario}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, number = {29}, pages = {E6890--E6899}, publisher = {National Academy of Sciences}, title = {{Genetic dissection of neuropeptide cell biology at high and low activity in a defined sensory neuron}}, doi = {10.1073/pnas.1714610115}, volume = {115}, year = {2018}, } @article{9135, abstract = {Idealized simulations of tropical moist convection have revealed that clouds can spontaneously clump together in a process called self-aggregation. This results in a state where a moist cloudy region with intense deep convection is surrounded by extremely dry subsiding air devoid of deep convection. Because of the idealized settings of the simulations where it was discovered, the relevance of self-aggregation to the real world is still debated. Here, we show that self-aggregation feedbacks play a leading-order role in the spontaneous genesis of tropical cyclones in cloud-resolving simulations. Those feedbacks accelerate the cyclogenesis process by a factor of 2, and the feedbacks contributing to the cyclone formation show qualitative and quantitative agreement with the self-aggregation process. Once the cyclone is formed, wind-induced surface heat exchange (WISHE) effects dominate, although we find that self-aggregation feedbacks have a small but nonnegligible contribution to the maintenance of the mature cyclone. Our results suggest that self-aggregation, and the framework developed for its study, can help shed more light into the physical processes leading to cyclogenesis and cyclone intensification. In particular, our results point out the importance of the longwave radiative cooling outside the cyclone.}, author = {Muller, Caroline J and Romps, David M.}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, keywords = {Multidisciplinary}, number = {12}, pages = {2930--2935}, publisher = {Proceedings of the National Academy of Sciences}, title = {{Acceleration of tropical cyclogenesis by self-aggregation feedbacks}}, doi = {10.1073/pnas.1719967115}, volume = {115}, year = {2018}, } @article{7729, abstract = {Quantifying the effects of inbreeding is critical to characterizing the genetic architecture of complex traits. This study highlights through theory and simulations the strengths and shortcomings of three SNP-based inbreeding measures commonly used to estimate inbreeding depression (ID). We demonstrate that heterogeneity in linkage disequilibrium (LD) between causal variants and SNPs biases ID estimates, and we develop an approach to correct this bias using LD and minor allele frequency stratified inference (LDMS). We quantified ID in 25 traits measured in ∼140,000 participants of the UK Biobank, using LDMS, and confirmed previously published ID for 4 traits. We find unique evidence of ID for handgrip strength, waist/hip ratio, and visual and auditory acuity (ID between −2.3 and −5.2 phenotypic SDs for complete inbreeding; P<0.001). Our results illustrate that a careful choice of the measure of inbreeding combined with LDMS stratification improves both detection and quantification of ID using SNP data.}, author = {Yengo, Loic and Zhu, Zhihong and Wray, Naomi R. and Weir, Bruce S. and Yang, Jian and Robinson, Matthew Richard and Visscher, Peter M.}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, number = {32}, pages = {8602--8607}, publisher = {Proceedings of the National Academy of Sciences}, title = {{Detection and quantification of inbreeding depression for complex traits from SNP data}}, doi = {10.1073/pnas.1621096114}, volume = {114}, year = {2017}, } @article{7757, abstract = {Recent advances in designing metamaterials have demonstrated that global mechanical properties of disordered spring networks can be tuned by selectively modifying only a small subset of bonds. Here, using a computationally efficient approach, we extend this idea to tune more general properties of networks. With nearly complete success, we are able to produce a strain between any two target nodes in a network in response to an applied source strain on any other pair of nodes by removing only ∼1% of the bonds. We are also able to control multiple pairs of target nodes, each with a different individual response, from a single source, and to tune multiple independent source/target responses simultaneously into a network. We have fabricated physical networks in macroscopic 2D and 3D systems that exhibit these responses. This work is inspired by the long-range coupled conformational changes that constitute allosteric function in proteins. The fact that allostery is a common means for regulation in biological molecules suggests that it is a relatively easy property to develop through evolution. In analogy, our results show that long-range coupled mechanical responses are similarly easy to achieve in disordered networks.}, author = {Rocks, Jason W. and Pashine, Nidhi and Bischofberger, Irmgard and Goodrich, Carl Peter and Liu, Andrea J. and Nagel, Sidney R.}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, number = {10}, pages = {2520--2525}, publisher = {Proceedings of the National Academy of Sciences}, title = {{Designing allostery-inspired response in mechanical networks}}, doi = {10.1073/pnas.1612139114}, volume = {114}, year = {2017}, } @article{7758, abstract = {Controlling motion at the microscopic scale is a fundamental goal in the development of biologically inspired systems. We show that the motion of active, self-propelled colloids can be sufficiently controlled for use as a tool to assemble complex structures such as braids and weaves out of microscopic filaments. Unlike typical self-assembly paradigms, these structures are held together by geometric constraints rather than adhesive bonds. The out-of-equilibrium assembly that we propose involves precisely controlling the 2D motion of active colloids so that their path has a nontrivial topology. We demonstrate with proof-of-principle Brownian dynamics simulations that, when the colloids are attached to long semiflexible filaments, this motion causes the filaments to braid. The ability of the active particles to provide sufficient force necessary to bend the filaments into a braid depends on a number of factors, including the self-propulsion mechanism, the properties of the filament, and the maximum curvature in the braid. Our work demonstrates that nonequilibrium assembly pathways can be designed using active particles.}, author = {Goodrich, Carl Peter and Brenner, Michael P.}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, number = {2}, pages = {257--262}, publisher = {Proceedings of the National Academy of Sciences}, title = {{Using active colloids as machines to weave and braid on the micrometer scale}}, doi = {10.1073/pnas.1608838114}, volume = {114}, year = {2017}, } @article{6113, author = {Oda, Shigekazu and Toyoshima, Yu and de Bono, Mario}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, number = {23}, pages = {E4658--E4665}, publisher = {National Academy of Sciences}, title = {{Modulation of sensory information processing by a neuroglobin in Caenorhabditis elegans}}, doi = {10.1073/pnas.1614596114}, volume = {114}, year = {2017}, } @article{6115, abstract = {Animals adjust their behavioral priorities according to momentary needs and prior experience. We show that Caenorhabditis elegans changes how it processes sensory information according to the oxygen environment it experienced recently. C. elegans acclimated to 7% O2 are aroused by CO2 and repelled by pheromones that attract animals acclimated to 21% O2. This behavioral plasticity arises from prolonged activity differences in a circuit that continuously signals O2 levels. A sustained change in the activity of O2-sensing neurons reprograms the properties of their postsynaptic partners, the RMG hub interneurons. RMG is gap-junctionally coupled to the ASK and ADL pheromone sensors that respectively drive pheromone attraction and repulsion. Prior O2 experience has opposite effects on the pheromone responsiveness of these neurons. These circuit changes provide a physiological correlate of altered pheromone valence. Our results suggest C. elegans stores a memory of recent O2 experience in the RMG circuit and illustrate how a circuit is flexibly sculpted to guide behavioral decisions in a context-dependent manner.}, author = {Fenk, Lorenz A. and de Bono, Mario}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, number = {16}, pages = {4195--4200}, publisher = {National Academy of Sciences}, title = {{Memory of recent oxygen experience switches pheromone valence inCaenorhabditis elegans}}, doi = {10.1073/pnas.1618934114}, volume = {114}, year = {2017}, } @article{8452, abstract = {During spore formation in Bacillus subtilis a transenvelope complex is assembled across the double membrane that separates the mother cell and forespore. This complex (called the “A–Q complex”) is required to maintain forespore development and is composed of proteins with remote homology to components of type II, III, and IV secretion systems found in Gram-negative bacteria. Here, we show that one of these proteins, SpoIIIAG, which has remote homology to ring-forming proteins found in type III secretion systems, assembles into an oligomeric ring in the periplasmic-like space between the two membranes. Three-dimensional reconstruction of images generated by cryo-electron microscopy indicates that the SpoIIIAG ring has a cup-and-saucer architecture with a 6-nm central pore. Structural modeling of SpoIIIAG generated a 24-member ring with dimensions similar to those of the EM-derived saucer. Point mutations in the predicted oligomeric interface disrupted ring formation in vitro and impaired forespore gene expression and efficient spore formation in vivo. Taken together, our data provide strong support for the model in which the A–Q transenvelope complex contains a conduit that connects the mother cell and forespore. We propose that a set of stacked rings spans the intermembrane space, as has been found for type III secretion systems.}, author = {Rodrigues, Christopher D. A. and Henry, Xavier and Neumann, Emmanuelle and Kurauskas, Vilius and Bellard, Laure and Fichou, Yann and Schanda, Paul and Schoehn, Guy and Rudner, David Z. and Morlot, Cecile}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, number = {41}, pages = {11585--11590}, publisher = {National Academy of Sciences}, title = {{A ring-shaped conduit connects the mother cell and forespore during sporulation in Bacillus subtilis}}, doi = {10.1073/pnas.1609604113}, volume = {113}, year = {2016}, } @article{7760, abstract = {We propose a Widom-like scaling ansatz for the critical jamming transition. Our ansatz for the elastic energy shows that the scaling of the energy, compressive strain, shear strain, system size, pressure, shear stress, bulk modulus, and shear modulus are all related to each other via scaling relations, with only three independent scaling exponents. We extract the values of these exponents from already known numerical or theoretical results, and we numerically verify the resulting predictions of the scaling theory for the energy and residual shear stress. We also derive a scaling relation between pressure and residual shear stress that yields insight into why the shear and bulk moduli scale differently. Our theory shows that the jamming transition exhibits an emergent scale invariance, setting the stage for the potential development of a renormalization group theory for jamming.}, author = {Goodrich, Carl Peter and Liu, Andrea J. and Sethna, James P.}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, number = {35}, pages = {9745--9750}, publisher = {Proceedings of the National Academy of Sciences}, title = {{Scaling ansatz for the jamming transition}}, doi = {10.1073/pnas.1601858113}, volume = {113}, year = {2016}, } @article{6118, abstract = {Carbon dioxide (CO2) gradients are ubiquitous and provide animals with information about their environment, such as the potential presence of prey or predators. The nematode Caenorhabditis elegans avoids elevated CO2, and previous work identified three neuron pairs called “BAG,” “AFD,” and “ASE” that respond to CO2 stimuli. Using in vivo Ca2+ imaging and behavioral analysis, we show that C. elegans can detect CO2 independently of these sensory pathways. Many of the C. elegans sensory neurons we examined, including the AWC olfactory neurons, the ASJ and ASK gustatory neurons, and the ASH and ADL nociceptors, respond to a rise in CO2 with a rise in Ca2+. In contrast, glial sheath cells harboring the sensory endings of C. elegans’ major chemosensory neurons exhibit strong and sustained decreases in Ca2+ in response to high CO2. Some of these CO2 responses appear to be cell intrinsic. Worms therefore may couple detection of CO2 to that of other cues at the earliest stages of sensory processing. We show that C. elegans persistently suppresses oviposition at high CO2. Hermaphrodite-specific neurons (HSNs), the executive neurons driving egg-laying, are tonically inhibited when CO2 is elevated. CO2 modulates the egg-laying system partly through the AWC olfactory neurons: High CO2 tonically activates AWC by a cGMP-dependent mechanism, and AWC output inhibits the HSNs. Our work shows that CO2 is a more complex sensory cue for C. elegans than previously thought, both in terms of behavior and neural circuitry.}, author = {Fenk, Lorenz A. and de Bono, Mario}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, number = {27}, pages = {E3525--E3534}, publisher = {National Academy of Sciences}, title = {{Environmental CO2 inhibits Caenorhabditis elegans egg-laying by modulating olfactory neurons and evokes widespread changes in neural activity}}, doi = {10.1073/pnas.1423808112}, volume = {112}, year = {2015}, } @article{6133, abstract = {cGMP signaling is widespread in the nervous system. However, it has proved difficult to visualize and genetically probe endogenously evoked cGMP dynamics in neurons in vivo. Here, we combine cGMP and Ca2+ biosensors to image and dissect a cGMP signaling network in a Caenorhabditis elegans oxygen-sensing neuron. We show that a rise in O2 can evoke a tonic increase in cGMP that requires an atypical O2-binding soluble guanylate cyclase and that is sustained until oxygen levels fall. Increased cGMP leads to a sustained Ca2+ response in the neuron that depends on cGMP-gated ion channels. Elevated levels of cGMP and Ca2+ stimulate competing negative feedback loops that shape cGMP dynamics. Ca2+-dependent negative feedback loops, including activation of phosphodiesterase-1 (PDE-1), dampen the rise of cGMP. A different negative feedback loop, mediated by phosphodiesterase-2 (PDE-2) and stimulated by cGMP-dependent kinase (PKG), unexpectedly promotes cGMP accumulation following a rise in O2, apparently by keeping in check gating of cGMP channels and limiting activation of Ca2+-dependent negative feedback loops. Simultaneous imaging of Ca2+ and cGMP suggests that cGMP levels can rise close to cGMP channels while falling elsewhere. O2-evoked cGMP and Ca2+ responses are highly reproducible when the same neuron in an individual animal is stimulated repeatedly, suggesting that cGMP transduction has high intrinsic reliability. However, responses vary substantially across individuals, despite animals being genetically identical and similarly reared. This variability may reflect stochastic differences in expression of cGMP signaling components. Our work provides in vivo insights into the architecture of neuronal cGMP signaling.}, author = {Couto, A. and Oda, S. and Nikolaev, V. O. and Soltesz, Z. and de Bono, Mario}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, number = {35}, pages = {E3301--E3310}, publisher = {Proceedings of the National Academy of Sciences}, title = {{In vivo genetic dissection of O2-evoked cGMP dynamics in a Caenorhabditis elegans gas sensor}}, doi = {10.1073/pnas.1217428110}, volume = {110}, year = {2013}, } @article{6137, abstract = {Variation in food quality and abundance requires animals to decide whether to stay on a poor food patch or leave in search of better food. An important question in behavioral ecology asks when is it optimal for an animal to leave a food patch it is depleting. Although optimal foraging is central to evolutionary success, the neural and molecular mechanisms underlying it are poorly understood. Here we investigate the neuronal basis for adaptive food-leaving behavior in response to resource depletion in Caenorhabditis elegans, and identify several of the signaling pathways involved. The ASE neurons, previously implicated in salt chemoattraction, promote food-leaving behavior via a cGMP pathway as food becomes limited. High ambient O2 promotes food-leaving via the O2-sensing neurons AQR, PQR, and URX. Ectopic activation of these neurons using channelrhodopsin is sufficient to induce high food-leaving behavior. In contrast, the neuropeptide receptor NPR-1, which regulates social behavior on food, acts in the ASE neurons, the nociceptive ASH neurons, and in the RMG interneuron to repress food-leaving. Finally, we show that neuroendocrine signaling by TGF-β/DAF-7 and neuronal insulin signaling are necessary for adaptive food-leaving behavior. We suggest that animals integrate information about their nutritional state with ambient oxygen and gustatory stimuli to formulate optimal foraging strategies.}, author = {Milward, K. and Busch, K. E. and Murphy, R. J. and de Bono, Mario and Olofsson, B.}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, number = {51}, pages = {20672--20677}, publisher = {National Academy of Sciences}, title = {{Neuronal and molecular substrates for optimal foraging in Caenorhabditis elegans}}, doi = {10.1073/pnas.1106134109}, volume = {108}, year = {2011}, } @article{6146, abstract = {Homeostasis of internal carbon dioxide (CO2) and oxygen (O2) levels is fundamental to all animals. Here we examine the CO2 response of the nematode Caenorhabditis elegans. This species inhabits rotting material, which typically has a broad CO2 concentration range. We show that well fed C. elegans avoid CO2 levels above 0.5%. Animals can respond to both absolute CO2 concentrations and changes in CO2 levels within seconds. Responses to CO2 do not reflect avoidance of acid pH but appear to define a new sensory response. Sensation of CO2 is promoted by the cGMP-gated ion channel subunits TAX-2 and TAX-4, but other pathways are also important. Robust CO2 avoidance in well fed animals requires inhibition of the DAF-16 forkhead transcription factor by the insulin-like receptor DAF-2. Starvation, which activates DAF-16, strongly suppresses CO2 avoidance. Exposure to hypoxia (<1% O2) also suppresses CO2 avoidance via activation of the hypoxia-inducible transcription factor HIF-1. The npr-1 215V allele of the naturally polymorphic neuropeptide receptor npr-1, besides inhibiting avoidance of high ambient O2 in feeding C. elegans, also promotes avoidance of high CO2. C. elegans integrates competing O2 and CO2 sensory inputs so that one response dominates. Food and allelic variation at NPR-1 regulate which response prevails. Our results suggest that multiple sensory inputs are coordinated by C. elegans to generate different coherent foraging strategies.}, author = {Bretscher, A. J. and Busch, K. E. and de Bono, Mario}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, number = {23}, pages = {8044--8049}, publisher = {Proceedings of the National Academy of Sciences}, title = {{A carbon dioxide avoidance behavior is integrated with responses to ambient oxygen and food in Caenorhabditis elegans}}, doi = {10.1073/pnas.0707607105}, volume = {105}, year = {2008}, }