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https://www.readbyqxmd.com/read/28332981/global-reorganisation-of-cis-regulatory-units-upon-lineage-commitment-of-human-embryonic-stem-cells
#1
Paula Freire-Pritchett, Stefan Schoenfelder, Csilla Várnai, Steven W Wingett, Jonathan Cairns, Amanda J Collier, Raquel García-Vílchez, Mayra Furlan-Magaril, Cameron S Osborne, Peter J Fraser, Peter J Rugg-Gunn, Mikhail Spivakov
Long-range cis-regulatory elements such as enhancers coordinate cell-specific transcriptional programmes by engaging in DNA looping interactions with target promoters. Deciphering the interplay between the promoter connectivity and activity of cis-regulatory elements during lineage commitment is crucial for understanding developmental transcriptional control. Here, we use Promoter Capture Hi-C to generate a high-resolution atlas of chromosomal interactions involving ~22,000 gene promoters in human pluripotent and lineage-committed cells, identifying putative target genes for known and predicted enhancer elements...
March 23, 2017: ELife
https://www.readbyqxmd.com/read/28332980/a-receptor-and-neuron-that-activate-a-circuit-limiting-sucrose-consumption
#2
Ryan M Joseph, Jennifer S Sun, Edric Tam, John R Carlson
The neural control of sugar consumption is critical for normal metabolism. In contrast to sugar-sensing taste neurons that promote consumption, we identify a taste neuron that limits sucrose consumption in Drosophila. Silencing of the neuron increases sucrose feeding; optogenetic activation decreases it. The feeding inhibition depends on the IR60b receptor, as shown by behavioral analysis and Ca2+ imaging of an IR60b mutant. The IR60b phenotype shows a high degree of chemical specificity when tested with a broad panel of tastants...
March 23, 2017: ELife
https://www.readbyqxmd.com/read/28332979/the-perk-arm-of-the-unfolded-protein-response-regulates-satellite-cell-mediated-skeletal-muscle-regeneration
#3
Guangyan Xiong, Sajedah M Hindi, Aman K Mann, Yann Simon Gallot, Kyle R Bohnert, Douglas R Cavener, Scott R Whittemore, Ashok Kumar
Regeneration of skeletal muscle in adults is mediated by satellite stem cells. Accumulation of misfolded proteins triggers endoplasmic reticulum stress that leads to unfolded protein response (UPR). The UPR is relayed to the cell through the activation of PERK, IRE1/XBP1, and ATF6. Here, we demonstrate that levels of PERK and IRE1 are increased in satellite cells upon muscle injury. Inhibition of PERK, but not the IRE1 arm of the UPR in satellite cells inhibits myofiber regeneration in adult mice. PERK is essential for the survival and differentiation of activated satellite cells into the myogenic lineage...
March 23, 2017: ELife
https://www.readbyqxmd.com/read/28332978/structural-reorganization-of-the-chromatin-remodeling-enzyme-chd1-upon-engagement-with-nucleosomes
#4
Ramasubramanian Sundaramoorthy, Amanda L Hughes, Vijender Singh, Nicola Wiechens, Daniel P Ryan, Hassane El-Mkami, Maxim Petoukhov, Dmitri I Svergun, Barbara Treutlein, Salina Quack, Monika Fischer, Jens Michaelis, Bettina Böttcher, David G Norman, Tom Owen-Hughes
The yeast Chd1 protein acts to position nucleosomes across genomes. Here we model the structure of the Chd1 protein in solution and when bound to nucleosomes. In the apo state the DNA binding domain contacts the edge of the nucleosome while in the presence of the non-hydrolyzable ATP analog, ADP-beryllium fluoride, we observe additional interactions between the ATPase domain and the adjacent DNA gyre 1.5 helical turns from the dyad axis of symmetry. Binding in this conformation involves unravelling the outer turn of nucleosomal DNA and requires substantial reorientation of the DNA binding domain with respect to the ATPase domains...
March 23, 2017: ELife
https://www.readbyqxmd.com/read/28327289/gene-regulatory-network-plasticity-predates-a-switch-in-function-of-a-conserved-transcription-regulator
#5
Isabel Nocedal, Eugenio Mancera, Alexander D Johnson
The rewiring of gene regulatory networks can generate phenotypic novelty. It remains an open question, however, how the large number of connections needed to form a novel network arise over evolutionary time. Here we address this question using the network controlled by the fungal transcription regulator Ndt80. This conserved protein has undergone a dramatic switch in function-from an ancestral role regulating sporulation to a derived role regulating biofilm formation. This switch in function corresponded to a large-scale rewiring of the genes regulated by Ndt80...
March 22, 2017: ELife
https://www.readbyqxmd.com/read/28327288/atrophin-controls-developmental-signaling-pathways-via-interactions-with-trithorax-like
#6
Kelvin Yeung, Ann Boija, Edvin Karlsson, Per-Henrik Holmqvist, Yonit Tsatskis, Ilaria Nisoli, Damian B Yap, Alireza Lorzadeh, Michelle Moksa, Martin Hirst, Samuel Aparicio, Manolis Fanto, Per Stenberg, Mattias Mannervik, Helen McNeill
Mutations in human Atrophin1, a transcriptional corepressor, cause dentatorubral-pallidoluysian atrophy, a neurodegenerative disease. Drosophila Atrophin (Atro) mutants display many phenotypes, including neurodegeneration, segmentation, patterning and planar polarity defects. Despite Atro's critical role in development and disease, relatively little is known about Atro's binding partners and downstream targets. We present the first genomic analysis of Atro using ChIP-seq against endogenous Atro. ChIP-seq identified 1300 potential direct targets of Atro including engrailed, and components of the Dpp and Notch signaling pathways...
March 22, 2017: ELife
https://www.readbyqxmd.com/read/28323620/discovery-of-novel-determinants-of-endothelial-lineage-using-chimeric-heterokaryons
#7
Wing Tak Wong, Gianfranco Matrone, XiaoYu Tian, Simion Alin Tomoiaga, Kin Fai Au, Shu Meng, Sayumi Yamazoe, Daniel Sieveking, Kaifu Chen, David M Burns, James K Chen, Helen M Blau, John P Cooke
We wish to identify determinants of endothelial lineage. Murine embryonic stem cells (mESC) were fused with human endothelial cells in stable, non-dividing, heterokaryons. Using RNA-seq it is possible to discriminate between human and mouse transcripts in these chimeric heterokaryons. We observed a temporal pattern of gene expression in the ESCs of the heterokaryons that recapitulated ontogeny, with early mesodermal factors being expressed before mature endothelial genes. A set of transcriptional factors not known to be involved in endothelial development was upregulated, one of which was POU class 3 homeobox 2 (Pou3f2)...
March 21, 2017: ELife
https://www.readbyqxmd.com/read/28323619/fast-spiking-gaba-circuit-dynamics-in-the-auditory-cortex-predict-recovery-of-sensory-processing-following-peripheral-nerve-damage
#8
Jennifer Resnik, Daniel B Polley
Cortical neurons remap their receptive fields and rescale sensitivity to spared peripheral inputs following sensory nerve damage. To address how these plasticity processes are coordinated over the course of functional recovery, we tracked receptive field reorganization, spontaneous activity, and response gain from individual principal neurons in the adult mouse auditory cortex over a 50-day period surrounding either moderate or massive auditory nerve damage. We related the day-by-day recovery of sound processing to dynamic changes in the strength of intracortical inhibition from parvalbumin-expressing (PV) inhibitory neurons...
March 21, 2017: ELife
https://www.readbyqxmd.com/read/28323618/contact-dependent-killing-by-caulobacter-crescentus-via-cell-surface-associated-glycine-zipper-proteins
#9
Leonor Garcia-Bayona, Monica S Guo, Michael T Laub
Most bacteria are in fierce competition with other species for limited nutrients. Some bacteria can kill nearby cells by secreting bacteriocins, a diverse group of proteinaceous antimicrobials. However, bacteriocins are typically freely diffusible, and so of little value to planktonic cells in aqueous environments. Here, we identify an atypical two-protein bacteriocin in the α-proteobacterium Caulobacter crescentus that is retained on the surface of producer cells where it mediates cell contact-dependent killing...
March 21, 2017: ELife
https://www.readbyqxmd.com/read/28323617/cryoem-structures-of-membrane-pore-and-prepore-complex-reveal-cytolytic-mechanism-of-pneumolysin
#10
Katharina van Pee, Alexander Neuhaus, Edoardo D'Imprima, Deryck J Mills, Werner Kühlbrandt, Özkan Yildiz
Many pathogenic bacteria produce pore-forming toxins to attack and kill human cells. We have determined the 4.5 Å structure of the ~2.2 MDa pore complex of pneumolysin, the main virulence factor of Streptococcus pneumoniae, by cryoEM. The pneumolysin pore is a 400 Å ring of 42 membrane-inserted monomers. Domain D3 of the soluble toxin refolds into two ~85 Å β-hairpins that traverse the lipid bilayer and assemble into a 168-strand β-barrel. The pore complex is stabilized by salt bridges between β-hairpins of adjacent subunits and an internal α-barrel...
March 21, 2017: ELife
https://www.readbyqxmd.com/read/28323615/stella-modulates-transcriptional-and-endogenous-retrovirus-programs-during-maternal-to-zygotic-transition
#11
Yun Huang, Jong Kyoung Kim, Dang Vinh Do, Caroline Lee, Christopher A Penfold, Jan J Zylicz, John C Marioni, Jamie A Hackett, M Azim Surani
The maternal-to-zygotic transition (MZT) marks the period when the embryonic genome is activated and acquires control of development. Maternally inherited factors play a key role in this critical developmental process, which occurs at the 2-cell stage in mice. We investigated the function of the maternally inherited factor STELLA (DPPA3) using single-cell/embryo approaches. We show that loss of maternal STELLA results in widespread transcriptional mis-regulation and a partial failure of MZT. Strikingly, activation of endogenous retroviruses (ERVs) is significantly impaired in Stella maternal/zygotic knockout embryos, which in turn leads to a failure to upregulate chimeric transcripts...
March 21, 2017: ELife
https://www.readbyqxmd.com/read/28323614/a-chloroplast-retrograde-signal-3-phosphoadenosine-5-phosphate-acts-as-a-secondary-messenger-in-abscisic-acid-signaling-in-stomatal-closure-and-germination
#12
Wannarat Pornsiriwong, Gonzalo M Estavillo, Kai Xun Chan, Estee E Tee, Diep Ganguly, Peter A Crisp, Su Yin Phua, Chenchen Zhao, Jiaen Qiu, Jiyoung Park, Miing Tiem Yong, Nazia Nisar, Arun Kumar Yadav, Benjamin Schwessinger, John Rathjen, Christopher I Cazzonelli, Philippa B Wilson, Matthew Gilliham, Zhong-Hua Chen, Barry J Pogson
Organelle-nuclear retrograde signaling regulates gene expression, but its roles in specialized cells and integration with hormonal signaling remain enigmatic. Here we show that the SAL1-PAP (3'-phosphoadenosine 5'- phosphate) retrograde pathway interacts with abscisic acid (ABA) signaling to regulate stomatal closure and seed germination in Arabidopsis. Genetically or exogenously manipulating PAP bypasses the canonical signaling components ABA Insensitive 1 (ABI1) and Open Stomata 1 (OST1); priming an alternative pathway that restores ABA-responsive gene expression, ROS bursts, ion channel function, stomatal closure and drought tolerance in ost1-2...
March 21, 2017: ELife
https://www.readbyqxmd.com/read/28322723/nucleosomes-influence-multiple-steps-during-replication-initiation
#13
Ishara F Azmi, Shinya Watanabe, Michael F Maloney, Sukhyun Kang, Jason A Belsky, David M MacAlpine, Craig L Peterson, Stephen P Bell
Eukaryotic replication origin licensing, activation and timing are influenced by chromatin but a mechanistic understanding is lacking. Using reconstituted nucleosomal DNA replication assays, we assessed the impact of nucleosomes on replication initiation. To generate distinct nucleosomal landscapes, different chromatin-remodeling enzymes (CREs) were used to remodel nucleosomes on origin-DNA templates. Nucleosomal organization influenced two steps of replication initiation: origin licensing and helicase activation...
March 21, 2017: ELife
https://www.readbyqxmd.com/read/28322189/toxoplasma-gondii-f-actin-forms-an-extensive-filamentous-network-required-for-material-exchange-and-parasite-maturation
#14
Javier Periz, Jamie Whitelaw, Clare Harding, Simon Gras, Mario Igor Del Rosario Minina, Fernanda Latorre-Barragan, Leandro Lemgruber, Madita Alice Reimer, Robert Insall, Aoife Heaslip, Markus Meissner
Apicomplexan actin is important during the parasite's life cycle. Its polymerization kinetics are unusual, permitting only short, unstable F-actin filaments. It has not been possible to study actin in vivo and so its physiological roles have remained obscure, leading to models distinct from conventional actin behaviour. Here a modified version of the commercially available Actin-Chromobody® was tested as a novel tool for visualising F-actin dynamics in Toxoplasma gondii. Cb labels filamentous actin structures within the parasite cytosol and labels an extensive F-actin network that connects parasites within the parasitophorous vacuole and allows vesicles to be exchanged between parasites...
March 21, 2017: ELife
https://www.readbyqxmd.com/read/28318489/deletion-of-the-mad2l1-spindle-assembly-checkpoint-gene-is-tolerated-in-mouse-models-of-acute-t-cell-lymphoma-and-hepatocellular-carcinoma
#15
Floris Foijer, Lee A Albacker, Bjorn Bakker, Diana C Spierings, Ying Yue, Stephanie Z Xie, Stephanie H Davis, Annegret Lutum-Jehle, Darin Takemoto, Brian Hare, Brinley Furey, Roderick T Bronson, Peter M Lansdorp, Allan Bradley, Peter K Sorger
Chromosome instability (CIN) is deleterious to normal cells because of the burden of aneuploidy. However, most human solid tumors have an abnormal karyotype implying that gain and loss of chromosomes by cancer cells confers a selective advantage. CIN can be induced in the mouse by inactivating the spindle assembly checkpoint. This is lethal in the germline but we show here that adult T cells and hepatocytes can survive conditional inactivation of the Mad2l1 SAC gene and resulting CIN. This causes rapid onset of acute lymphoblastic leukemia (T-ALL) and progressive development of hepatocellular carcinoma (HCC), both lethal diseases...
March 20, 2017: ELife
https://www.readbyqxmd.com/read/28318488/computational-models-of-o-lm-cells-are-recruited-by-low-or-high-theta-frequency-inputs-depending-on-h-channel-distributions
#16
Vladislav Sekulić, Frances K Skinner
Although biophysical details of inhibitory neurons are becoming known, it is challenging to map these details onto function. Oriens-lacunosum/moleculare (O-LM) cells are inhibitory cells in the hippocampus that gate information flow, firing while phase-locked to theta rhythms. We build on our existing computational model database of O-LM cells to link model with function. We place our models in high-conductance states and modulate inhibitory inputs at a wide range of frequencies. We find preferred spiking recruitment of models at high (4-9 Hz) or low (2-5 Hz) theta depending on, respectively, the presence or absence of h-channels on their dendrites...
March 20, 2017: ELife
https://www.readbyqxmd.com/read/28318487/a-high-resolution-map-of-transcriptional-repression
#17
Ziwei Liang, Karen Brown, Thomas Carroll, Benjamin Taylor, Isabel Ferreirós Vidal, Brian Hendrich, David Rueda, Amanda G Fisher, Matthias Merkenschlager
Turning genes on and off is essential for development and homeostasis, yet little is known about the sequence and causal role of chromatin state changes during the repression of active genes. This is surprising, as defective gene silencing underlies developmental abnormalities and disease. Here we delineate the sequence and functional contribution of transcriptional repression mechanisms at high temporal resolution. Inducible entry of the NuRD-interacting transcriptional regulator Ikaros into mouse pre-B cell nuclei triggered immediate binding to target gene promoters...
March 20, 2017: ELife
https://www.readbyqxmd.com/read/28318486/structural-basis-of-transcription-arrest-by-coliphage-hk022-nun-in-an-escherichia-coli-rna-polymerase-elongation-complex
#18
Jin Young Kang, Paul Dominic B Olinares, James Chen, Elizabeth A Campbell, Arkady Mustaev, Brian T Chait, Max E Gottesman, Seth A Darst
Coliphage HK022 Nun blocks superinfection by coliphage λ by stalling RNA polymerase (RNAP) translocation specifically on λΔNA.To provide a structural framework to understand how Nun blocks RNAP translocation, we determined structures of Escherichia coli RNAP ternary elongation complexes (TECs) with and without Nun by single-particle cryo-electron microscopy. Nun fits tightly into the TEC by taking advantage of gaps between the RNAP and the nucleic acids. The C-terminal segment of Nun interacts with the RNAP β and β' subunits inside the RNAP active site cleft as well as with nearly every element of the nucleic-acid scaffold, essentially crosslinking the RNAP and the nucleic acids to prevent translocation, a mechanism supported by the effects of Nun amino acid substitutions...
March 20, 2017: ELife
https://www.readbyqxmd.com/read/28315525/insights-into-the-molecular-architecture-and-histone-h3-h4-deposition-mechanism-of-yeast-chromatin-assembly-factor-1
#19
Paul Victor Sauer, Jennifer Timm, Danni Liu, David Sitbon, Elisabetta Boeri-Erba, Christophe Velours, Norbert Mücke, Jörg Langowski, Françoise Ochsenbein, Geneviève Almouzni, Daniel Panne
How the very first step in nucleosome assembly, deposition of histone H3-H4 as tetramers or dimers on DNA, is accomplished remains largely unclear. Here we report that yeast chromatin assembly factor 1 (CAF1), a conserved histone chaperone complex that deposits H3-H4 during DNA replication, binds a single H3-H4 heterodimer in solution. We identify a new DNA binding domain in the large Cac1 subunit of CAF1, which is required for high-affinity DNA binding by the CAF1 three-subunit complex, and which is distinct from the previously described C-terminal winged-helix domain...
March 18, 2017: ELife
https://www.readbyqxmd.com/read/28315524/a-cellular-mechanism-for-inverse-effectiveness-in-multisensory-integration
#20
Torrey Ls Truszkowski, Oscar A Carrillo, Julia Bleier, Carolina Ramirez-Vizcarrondo, Molly McQuillan, Christopher P Truszkowski, Arseny S Khakhalin, Carlos D Aizenman
To build a coherent view of the external world, an organism needs to integrate multiple types of sensory information from different sources, a process known as multisensory integration (MSI). In a prior study (Felch et al. 2016) we showed that the temporal dependence of MSI in the optic tectum of Xenopus laevis tadpoles is mediated by the network dynamics of the recruitment of local inhibition by sensory input. This was one of the first cellular-level mechanisms described for MSI. Here we expand this cellular level view of MSI by focusing on the principle of inverse effectiveness, another central feature of MSI stating that the amount of multisensory enhancement observed inversely depends on the size of unisensory responses...
March 18, 2017: ELife
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