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https://www.readbyqxmd.com/read/29456082/identification-of-pirna-binding-sites-reveals-the-argonaute-regulatory-landscape-of-the-c-elegans-germline
#1
En-Zhi Shen, Hao Chen, Ahmet R Ozturk, Shikui Tu, Masaki Shirayama, Wen Tang, Yue-He Ding, Si-Yuan Dai, Zhiping Weng, Craig C Mello
piRNAs (Piwi-interacting small RNAs) engage Piwi Argonautes to silence transposons and promote fertility in animal germlines. Genetic and computational studies have suggested that C. elegans piRNAs tolerate mismatched pairing and in principle could target every transcript. Here we employ in vivo cross-linking to identify transcriptome-wide interactions between piRNAs and target RNAs. We show that piRNAs engage all germline mRNAs and that piRNA binding follows microRNA-like pairing rules. Targeting correlates better with binding energy than with piRNA abundance, suggesting that piRNA concentration does not limit targeting...
February 10, 2018: Cell
https://www.readbyqxmd.com/read/29456083/placeholder-nucleosomes-underlie-germline-to-embryo-dna-methylation-reprogramming
#2
Patrick J Murphy, Shan Fu Wu, Cody R James, Candice L Wike, Bradley R Cairns
The fate and function of epigenetic marks during the germline-to-embryo transition is a key issue in developmental biology, with relevance to stem cell programming and transgenerational inheritance. In zebrafish, DNA methylation patterns are programmed in transcriptionally quiescent cleavage embryos; paternally inherited patterns are maintained, whereas maternal patterns are reprogrammed to match the paternal. Here, we provide the mechanism by demonstrating that "Placeholder" nucleosomes, containing histone H2A variant H2A...
February 9, 2018: Cell
https://www.readbyqxmd.com/read/29456084/rescue-of-fragile-x-syndrome-neurons-by-dna-methylation-editing-of-the-fmr1-gene
#3
X Shawn Liu, Hao Wu, Marine Krzisch, Xuebing Wu, John Graef, Julien Muffat, Denes Hnisz, Charles H Li, Bingbing Yuan, Chuanyun Xu, Yun Li, Dan Vershkov, Angela Cacace, Richard A Young, Rudolf Jaenisch
Fragile X syndrome (FXS), the most common genetic form of intellectual disability in males, is caused by silencing of the FMR1 gene associated with hypermethylation of the CGG expansion mutation in the 5' UTR of FMR1 in FXS patients. Here, we applied recently developed DNA methylation editing tools to reverse this hypermethylation event. Targeted demethylation of the CGG expansion by dCas9-Tet1/single guide RNA (sgRNA) switched the heterochromatin status of the upstream FMR1 promoter to an active chromatin state, restoring a persistent expression of FMR1 in FXS iPSCs...
February 8, 2018: Cell
https://www.readbyqxmd.com/read/29429633/nk-cells-stimulate-recruitment-of-cdc1-into-the-tumor-microenvironment-promoting-cancer-immune-control
#4
Jan P Böttcher, Eduardo Bonavita, Probir Chakravarty, Hanna Blees, Mar Cabeza-Cabrerizo, Stefano Sammicheli, Neil C Rogers, Erik Sahai, Santiago Zelenay, Caetano Reis E Sousa
Conventional type 1 dendritic cells (cDC1) are critical for antitumor immunity, and their abundance within tumors is associated with immune-mediated rejection and the success of immunotherapy. Here, we show that cDC1 accumulation in mouse tumors often depends on natural killer (NK) cells that produce the cDC1 chemoattractants CCL5 and XCL1. Similarly, in human cancers, intratumoral CCL5, XCL1, and XCL2 transcripts closely correlate with gene signatures of both NK cells and cDC1 and are associated with increased overall patient survival...
February 6, 2018: Cell
https://www.readbyqxmd.com/read/29456081/lysozyme-counteracts-%C3%AE-lactam-antibiotics-by-promoting-the-emergence-of-l-form-bacteria
#5
Yoshikazu Kawai, Katarzyna Mickiewicz, Jeff Errington
β-lactam antibiotics inhibit bacterial cell wall assembly and, under classical microbiological culture conditions that are generally hypotonic, induce explosive cell death. Here, we show that under more physiological, osmoprotective conditions, for various Gram-positive bacteria, lysis is delayed or abolished, apparently because inhibition of class A penicillin-binding protein leads to a block in autolytic activity. Although these cells still then die by other mechanisms, exogenous lytic enzymes, such as lysozyme, can rescue viability by enabling the escape of cell wall-deficient "L-form" bacteria...
January 31, 2018: Cell
https://www.readbyqxmd.com/read/29398115/in-situ-structure-of-neuronal-c9orf72-poly-ga-aggregates-reveals-proteasome-recruitment
#6
Qiang Guo, Carina Lehmer, Antonio Martínez-Sánchez, Till Rudack, Florian Beck, Hannelore Hartmann, Manuela Pérez-Berlanga, Frédéric Frottin, Mark S Hipp, F Ulrich Hartl, Dieter Edbauer, Wolfgang Baumeister, Rubén Fernández-Busnadiego
Protein aggregation and dysfunction of the ubiquitin-proteasome system are hallmarks of many neurodegenerative diseases. Here, we address the elusive link between these phenomena by employing cryo-electron tomography to dissect the molecular architecture of protein aggregates within intact neurons at high resolution. We focus on the poly-Gly-Ala (poly-GA) aggregates resulting from aberrant translation of an expanded GGGGCC repeat in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia...
January 31, 2018: Cell
https://www.readbyqxmd.com/read/29398114/dopamine-secretion-is-mediated-by-sparse-active-zone-like-release-sites
#7
Changliang Liu, Lauren Kershberg, Jiexin Wang, Shirin Schneeberger, Pascal S Kaeser
Dopamine controls essential brain functions through volume transmission. Different from fast synaptic transmission, where neurotransmitter release and receptor activation are tightly coupled by an active zone, dopamine transmission is widespread and may not necessitate these organized release sites. Here, we determine whether striatal dopamine secretion employs specialized machinery for release. Using super resolution microscopy, we identified co-clustering of the active zone scaffolding proteins bassoon, RIM and ELKS in ∼30% of dopamine varicosities...
January 31, 2018: Cell
https://www.readbyqxmd.com/read/29398116/dynamic-ligand-discrimination-in-the-notch-signaling-pathway
#8
Nagarajan Nandagopal, Leah A Santat, Lauren LeBon, David Sprinzak, Marianne E Bronner, Michael B Elowitz
The Notch signaling pathway comprises multiple ligands that are used in distinct biological contexts. In principle, different ligands could activate distinct target programs in signal-receiving cells, but it is unclear how such ligand discrimination could occur. Here, we show that cells use dynamics to discriminate signaling by the ligands Dll1 and Dll4 through the Notch1 receptor. Quantitative single-cell imaging revealed that Dll1 activates Notch1 in discrete, frequency-modulated pulses that specifically upregulate the Notch target gene Hes1...
January 30, 2018: Cell
https://www.readbyqxmd.com/read/29398113/circuit-design-features-of-a-stable-two-cell-system
#9
Xu Zhou, Ruth A Franklin, Miri Adler, Jeremy B Jacox, Will Bailis, Justin A Shyer, Richard A Flavell, Avi Mayo, Uri Alon, Ruslan Medzhitov
Cell communication within tissues is mediated by multiple paracrine signals including growth factors, which control cell survival and proliferation. Cells and the growth factors they produce and receive constitute a circuit with specific properties that ensure homeostasis. Here, we used computational and experimental approaches to characterize the features of cell circuits based on growth factor exchange between macrophages and fibroblasts, two cell types found in most mammalian tissues. We found that the macrophage-fibroblast cell circuit is stable and robust to perturbations...
January 30, 2018: Cell
https://www.readbyqxmd.com/read/29395327/cloning-of-macaque-monkeys-by-somatic-cell-nuclear-transfer
#10
Zhen Liu, Yijun Cai, Yan Wang, Yanhong Nie, Chenchen Zhang, Yuting Xu, Xiaotong Zhang, Yong Lu, Zhanyang Wang, Muming Poo, Qiang Sun
Generation of genetically uniform non-human primates may help to establish animal models for primate biology and biomedical research. In this study, we have successfully cloned cynomolgus monkeys (Macaca fascicularis) by somatic cell nuclear transfer (SCNT). We found that injection of H3K9me3 demethylase Kdm4d mRNA and treatment with histone deacetylase inhibitor trichostatin A at one-cell stage following SCNT greatly improved blastocyst development and pregnancy rate of transplanted SCNT embryos in surrogate monkeys...
January 20, 2018: Cell
https://www.readbyqxmd.com/read/29398112/5-ht2c-receptor-structures-reveal-the-structural-basis-of-gpcr-polypharmacology
#11
Yao Peng, John D McCorvy, Kasper Harpsøe, Katherine Lansu, Shuguang Yuan, Petr Popov, Lu Qu, Mengchen Pu, Tao Che, Louise F Nikolajsen, Xi-Ping Huang, Yiran Wu, Ling Shen, Walden E Bjørn-Yoshimoto, Kang Ding, Daniel Wacker, Gye Won Han, Jianjun Cheng, Vsevolod Katritch, Anders A Jensen, Michael A Hanson, Suwen Zhao, David E Gloriam, Bryan L Roth, Raymond C Stevens, Zhi-Jie Liu
Drugs frequently require interactions with multiple targets-via a process known as polypharmacology-to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT2A-C receptor-selective inverse agonist ritanserin at resolutions of 3...
January 19, 2018: Cell
https://www.readbyqxmd.com/read/29395328/cd10-gpr77-cancer-associated-fibroblasts-promote-cancer-formation-and-chemoresistance-by-sustaining-cancer-stemness
#12
Shicheng Su, Jianing Chen, Herui Yao, Jiang Liu, Shubin Yu, Liyan Lao, Minghui Wang, Manli Luo, Yue Xing, Fei Chen, Di Huang, Jinghua Zhao, Linbin Yang, Dan Liao, Fengxi Su, Mengfeng Li, Qiang Liu, Erwei Song
Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10+GPR77+ CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10+GPR77+ CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor...
January 18, 2018: Cell
https://www.readbyqxmd.com/read/29358051/non-classical-immunity-controls-microbiota-impact-on-skin-immunity-and-tissue-repair
#13
Jonathan L Linehan, Oliver J Harrison, Seong-Ji Han, Allyson L Byrd, Ivan Vujkovic-Cvijin, Alejandro V Villarino, Shurjo K Sen, Jahangheer Shaik, Margery Smelkinson, Samira Tamoutounour, Nicholas Collins, Nicolas Bouladoux, Amiran Dzutsev, Stephan P Rosshart, Jesse H Arbuckle, Chyung-Ru Wang, Thomas M Kristie, Barbara Rehermann, Giorgio Trinchieri, Jason M Brenchley, John J O'Shea, Yasmine Belkaid
Mammalian barrier surfaces are constitutively colonized by numerous microorganisms. We explored how the microbiota was sensed by the immune system and the defining properties of such responses. Here, we show that a skin commensal can induce T cell responses in a manner that is restricted to non-classical MHC class I molecules. These responses are uncoupled from inflammation and highly distinct from pathogen-induced cells. Commensal-specific T cells express a defined gene signature that is characterized by expression of effector genes together with immunoregulatory and tissue-repair signatures...
January 15, 2018: Cell
https://www.readbyqxmd.com/read/29395325/human-adar1-prevents-endogenous-rna-from-triggering-translational-shutdown
#14
Hachung Chung, Jorg J A Calis, Xianfang Wu, Tony Sun, Yingpu Yu, Stephanie L Sarbanes, Viet Loan Dao Thi, Abigail R Shilvock, H-Heinrich Hoffmann, Brad R Rosenberg, Charles M Rice
Type I interferon (IFN) is produced when host sensors detect foreign nucleic acids, but how sensors differentiate self from nonself nucleic acids, such as double-stranded RNA (dsRNA), is incompletely understood. Mutations in ADAR1, an adenosine-to-inosine editing enzyme of dsRNA, cause Aicardi-Goutières syndrome, an autoinflammatory disorder associated with spontaneous interferon production and neurologic sequelae. We generated ADAR1 knockout human cells to explore ADAR1 substrates and function. ADAR1 primarily edited Alu elements in RNA polymerase II (pol II)-transcribed mRNAs, but not putative pol III-transcribed Alus...
January 12, 2018: Cell
https://www.readbyqxmd.com/read/29361316/structure-and-conformational-dynamics-of-the-human-spliceosomal-bact-complex
#15
David Haselbach, Ilya Komarov, Dmitry E Agafonov, Klaus Hartmuth, Benjamin Graf, Olexandr Dybkov, Henning Urlaub, Berthold Kastner, Reinhard Lührmann, Holger Stark
The spliceosome is a highly dynamic macromolecular complex that precisely excises introns from pre-mRNA. Here we report the cryo-EM 3D structure of the human Bact spliceosome at 3.4 Å resolution. In the Bact state, the spliceosome is activated but not catalytically primed, so that it is functionally blocked prior to the first catalytic step of splicing. The spliceosomal core is similar to the yeast Bact spliceosome; important differences include the presence of the RNA helicase aquarius and peptidyl prolyl isomerases...
January 12, 2018: Cell
https://www.readbyqxmd.com/read/29358050/multiscale-structuring-of-the-e-%C3%A2-coli-chromosome-by-nucleoid-associated-and-condensin-proteins
#16
Virginia S Lioy, Axel Cournac, Martial Marbouty, Stéphane Duigou, Julien Mozziconacci, Olivier Espéli, Frédéric Boccard, Romain Koszul
As in eukaryotes, bacterial genomes are not randomly folded. Bacterial genetic information is generally carried on a circular chromosome with a single origin of replication from which two replication forks proceed bidirectionally toward the opposite terminus region. Here, we investigate the higher-order architecture of the Escherichia coli genome, showing its partition into two structurally distinct entities by a complex and intertwined network of contacts: the replication terminus (ter) region and the rest of the chromosome...
January 10, 2018: Cell
https://www.readbyqxmd.com/read/29358049/ultraconserved-enhancers-are-required-for-normal-development
#17
Diane E Dickel, Athena R Ypsilanti, Ramón Pla, Yiwen Zhu, Iros Barozzi, Brandon J Mannion, Yupar S Khin, Yoko Fukuda-Yuzawa, Ingrid Plajzer-Frick, Catherine S Pickle, Elizabeth A Lee, Anne N Harrington, Quan T Pham, Tyler H Garvin, Momoe Kato, Marco Osterwalder, Jennifer A Akiyama, Veena Afzal, John L R Rubenstein, Len A Pennacchio, Axel Visel
Non-coding "ultraconserved" regions containing hundreds of consecutive bases of perfect sequence conservation across mammalian genomes can function as distant-acting enhancers. However, initial deletion studies in mice revealed that loss of such extraordinarily constrained sequences had no immediate impact on viability. Here, we show that ultraconserved enhancers are required for normal development. Focusing on some of the longest ultraconserved sites genome wide, located near the essential neuronal transcription factor Arx, we used genome editing to create an expanded series of knockout mice lacking individual or combinations of ultraconserved enhancers...
January 10, 2018: Cell
https://www.readbyqxmd.com/read/29358048/establishment-of-dna-dna-interactions-by-the-cohesin-ring
#18
Yasuto Murayama, Catarina P Samora, Yumiko Kurokawa, Hiroshi Iwasaki, Frank Uhlmann
The ring-shaped structural maintenance of chromosome (SMC) complexes are multi-subunit ATPases that topologically encircle DNA. SMC rings make vital contributions to numerous chromosomal functions, including mitotic chromosome condensation, sister chromatid cohesion, DNA repair, and transcriptional regulation. They are thought to do so by establishing interactions between more than one DNA. Here, we demonstrate DNA-DNA tethering by the purified fission yeast cohesin complex. DNA-bound cohesin efficiently and topologically captures a second DNA, but only if that is single-stranded DNA (ssDNA)...
January 10, 2018: Cell
https://www.readbyqxmd.com/read/29336888/lxr-apoe-activation-restricts-innate-immune-suppression-in-cancer
#19
Masoud F Tavazoie, Ilana Pollack, Raissa Tanqueco, Benjamin N Ostendorf, Bernardo S Reis, Foster C Gonsalves, Isabel Kurth, Celia Andreu-Agullo, Mark L Derbyshire, Jessica Posada, Shugaku Takeda, Kimia N Tafreshian, Eric Rowinsky, Michael Szarek, Roger J Waltzman, Elizabeth A Mcmillan, Connie Zhao, Monica Mita, Alain Mita, Bartosz Chmielowski, Michael A Postow, Antoni Ribas, Daniel Mucida, Sohail F Tavazoie
Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)-an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial...
January 9, 2018: Cell
https://www.readbyqxmd.com/read/29395326/breaching-self-tolerance-to-alu-duplex-rna-underlies-mda5-mediated-inflammation
#20
Sadeem Ahmad, Xin Mu, Fei Yang, Emily Greenwald, Ji Woo Park, Etai Jacob, Cheng-Zhong Zhang, Sun Hur
Aberrant activation of innate immune receptors can cause a spectrum of immune disorders, such as Aicardi-Goutières syndrome (AGS). One such receptor is MDA5, a viral dsRNA sensor that induces antiviral immune response. Using a newly developed RNase-protection/RNA-seq approach, we demonstrate here that constitutive activation of MDA5 in AGS results from the loss of tolerance to cellular dsRNAs formed by Alu retroelements. While wild-type MDA5 cannot efficiently recognize Alu-dsRNAs because of its limited filament formation on imperfect duplexes, AGS variants of MDA5 display reduced sensitivity to duplex structural irregularities, assembling signaling-competent filaments on Alu-dsRNAs...
January 8, 2018: Cell
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