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Valentina Lo Sardo, Pavel Chubukov, William Ferguson, Aditya Kumar, Evan L Teng, Michael Duran, Lei Zhang, Gregory Cost, Adam J Engler, Fyodor Urnov, Eric J Topol, Ali Torkamani, Kristin K Baldwin
The 9p21.3 cardiovascular disease locus is the most influential common genetic risk factor for coronary artery disease (CAD), accounting for ∼10%-15% of disease in non-African populations. The ∼60 kb risk haplotype is human-specific and lacks coding genes, hindering efforts to decipher its function. Here, we produce induced pluripotent stem cells (iPSCs) from risk and non-risk individuals, delete each haplotype using genome editing, and generate vascular smooth muscle cells (VSMCs). Risk VSMCs exhibit globally altered transcriptional networks that intersect with previously identified CAD risk genes and pathways, concomitant with aberrant adhesion, contraction, and proliferation...
December 6, 2018: Cell
Nicolás Rascovan, Karl-Göran Sjögren, Kristian Kristiansen, Rasmus Nielsen, Eske Willerslev, Christelle Desnues, Simon Rasmussen
Between 5,000 and 6,000 years ago, many Neolithic societies declined throughout western Eurasia due to a combination of factors that are still largely debated. Here, we report the discovery and genome reconstruction of Yersiniapestis, the etiological agent of plague, in Neolithic farmers in Sweden, pre-dating and basal to all modern and ancient known strains of this pathogen. We investigated the history of this strain by combining phylogenetic and molecular clock analyses of the bacterial genome, detailed archaeological information, and genomic analyses from infected individuals and hundreds of ancient human samples across Eurasia...
December 5, 2018: Cell
Jakob Trendel, Thomas Schwarzl, Rastislav Horos, Ananth Prakash, Alex Bateman, Matthias W Hentze, Jeroen Krijgsveld
Proteins and RNA functionally and physically intersect in multiple biological processes, however, currently no universal method is available to purify protein-RNA complexes. Here, we introduce XRNAX, a method for the generic purification of protein-crosslinked RNA, and demonstrate its versatility to study the composition and dynamics of protein-RNA interactions by various transcriptomic and proteomic approaches. We show that XRNAX captures all RNA biotypes and use this to characterize the sub-proteomes that interact with coding and non-coding RNAs (ncRNAs) and to identify hundreds of protein-RNA interfaces...
December 1, 2018: Cell
Minhee Park, Nikit Patel, Albert J Keung, Ahmad S Khalil
Chemical modifications to DNA and histone proteins are involved in epigenetic programs underlying cellular differentiation and development. Regulatory networks involving molecular writers and readers of chromatin marks are thought to control these programs. Guided by this common principle, we established an orthogonal epigenetic regulatory system in mammalian cells using N6-methyladenine (m6A), a DNA modification not commonly found in metazoan epigenomes. Our system utilizes synthetic factors that write and read m6A and consequently recruit transcriptional regulators to control reporter loci...
November 29, 2018: Cell
Federico Rojas, Eleanor Silvester, Julie Young, Rachel Milne, Mabel Tettey, Douglas R Houston, Malcolm D Walkinshaw, Irene Pérez-Pi, Manfred Auer, Helen Denton, Terry K Smith, Joanne Thompson, Keith R Matthews
Trypanosome parasites control their virulence and spread by using quorum sensing (QS) to generate transmissible "stumpy forms" in their host bloodstream. However, the QS signal "stumpy induction factor" (SIF) and its reception mechanism are unknown. Although trypanosomes lack G protein-coupled receptor signaling, we have identified a surface GPR89-family protein that regulates stumpy formation. TbGPR89 is expressed on bloodstream "slender form" trypanosomes, which receive the SIF signal, and when ectopically expressed, TbGPR89 drives stumpy formation in a SIF-pathway-dependent process...
November 27, 2018: Cell
Amar N Mirza, Siegen A McKellar, Nicole M Urman, Alexander S Brown, Tyler Hollmig, Sumaira Z Aasi, Anthony E Oro
Understanding transcription factor navigation through the nucleus remains critical for developing targeted therapeutics. The GLI1 transcription factor must maintain maximal Hedgehog pathway output in basal cell carcinomas (BCCs), and we have previously shown that resistant BCCs increase GLI1 deacetylation through atypical protein kinase Cι/λ (aPKC) and HDAC1. Here we identify a lamina-associated polypeptide 2 (LAP2) isoform-dependent nuclear chaperoning system that regulates GLI1 movement between the nuclear lamina and nucleoplasm to achieve maximal activation...
November 27, 2018: Cell
Michael D Vahey, Daniel A Fletcher
Influenza viruses inhabit a wide range of host environments using a limited repertoire of protein components. Unlike viruses with stereotyped shapes, influenza produces virions with significant morphological variability even within clonal populations. Whether this tendency to form pleiomorphic virions is coupled to compositional heterogeneity and whether it affects replicative fitness remains unclear. Here, we address these questions by developing a strain of influenza A virus amenable to rapid compositional characterization through quantitative, site-specific labeling of viral proteins...
November 27, 2018: Cell
Lilan You, Jun Ma, Jiuyu Wang, Daria Artamonova, Min Wang, Liang Liu, Hua Xiang, Konstantin Severinov, Xinzheng Zhang, Yanli Wang
Csm, a type III-A CRISPR-Cas interference complex, is a CRISPR RNA (crRNA)-guided RNase that also possesses target RNA-dependent DNase and cyclic oligoadenylate (cOA) synthetase activities. However, the structural features allowing target RNA-binding-dependent activation of DNA cleavage and cOA generation remain unknown. Here, we report the structure of Csm in complex with crRNA together with structures of cognate or non-cognate target RNA bound Csm complexes. We show that depending on complementarity with the 5' tag of crRNA, the 3' anti-tag region of target RNA binds at two distinct sites of the Csm complex...
November 26, 2018: Cell
Lu O Sun, Sara B Mulinyawe, Hannah Y Collins, Adiljan Ibrahim, Qingyun Li, David J Simon, Marc Tessier-Lavigne, Ben A Barres
Nervous system function depends on proper myelination for insulation and critical trophic support for axons. Myelination is tightly regulated spatially and temporally, but how it is controlled molecularly remains largely unknown. Here, we identified key molecular mechanisms governing the regional and temporal specificity of CNS myelination. We show that transcription factor EB (TFEB) is highly expressed by differentiating oligodendrocytes and that its loss causes precocious and ectopic myelination in many parts of the murine brain...
November 21, 2018: Cell
Ursula Quitterer, Xuebin Fu, Armin Pohl, Karam M Bayoumy, Andreas Langer, Said AbdAlla
Preeclampsia is the most frequent pregnancy-related complication worldwide with no cure. While a number of molecular features have emerged, the underlying causal mechanisms behind the disorder remain obscure. Here, we find that increased complex formation between angiotensin II AT1 and bradykinin B2, two G protein-coupled receptors with opposing effects on blood vessel constriction, triggers symptoms of preeclampsia in pregnant mice. Aberrant heteromerization of AT1-B2 led to exaggerated calcium signaling and high vascular smooth muscle mechanosensitivity, which could explain the onset of preeclampsia symptoms at late-stage pregnancy as mechanical forces increase with fetal mass...
November 20, 2018: Cell
Stefano Stella, Pablo Mesa, Johannes Thomsen, Bijoya Paul, Pablo Alcón, Simon B Jensen, Bhargav Saligram, Matias E Moses, Nikos S Hatzakis, Guillermo Montoya
Cas12a, also known as Cpf1, is a type V-A CRISPR-Cas RNA-guided endonuclease that is used for genome editing based on its ability to generate specific dsDNA breaks. Here, we show cryo-EM structures of intermediates of the cleavage reaction, thus visualizing three protein regions that sense the crRNA-DNA hybrid assembly triggering the catalytic activation of Cas12a. Single-molecule FRET provides the thermodynamics and kinetics of the conformational activation leading to phosphodiester bond hydrolysis. These findings illustrate why Cas12a cuts its target DNA and unleashes unspecific cleavage activity, degrading ssDNA molecules after activation...
November 15, 2018: Cell
Erin M Gibson, Surya Nagaraja, Alfonso Ocampo, Lydia T Tam, Lauren S Wood, Praveen N Pallegar, Jacob J Greene, Anna C Geraghty, Andrea K Goldstein, Lijun Ni, Pamelyn J Woo, Ben A Barres, Shane Liddelow, Hannes Vogel, Michelle Monje
Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell dysfunction and white matter dysfunction are thought to contribute to this debilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing a mouse model of methotrexate chemotherapy-induced neurological dysfunction, we find a similar depletion of white matter OPCs, increased but incomplete OPC differentiation, and a persistent deficit in myelination...
November 13, 2018: Cell
Pascale André, Caroline Denis, Caroline Soulas, Clarisse Bourbon-Caillet, Julie Lopez, Thomas Arnoux, Mathieu Bléry, Cécile Bonnafous, Laurent Gauthier, Ariane Morel, Benjamin Rossi, Romain Remark, Violette Breso, Elodie Bonnet, Guillaume Habif, Sophie Guia, Ana Ines Lalanne, Caroline Hoffmann, Olivier Lantz, Jérôme Fayette, Agnès Boyer-Chammard, Robert Zerbib, Pierre Dodion, Hormas Ghadially, Maria Jure-Kunkel, Yannis Morel, Ronald Herbst, Emilie Narni-Mancinelli, Roger B Cohen, Eric Vivier
Checkpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8+ T cell effector functions in mice and humans. Monalizumab, a humanized anti-NKG2A antibody, enhanced NK cell activity against various tumor cells and rescued CD8+ T cell function in combination with PD-x axis blockade. Monalizumab also stimulated NK cell activity against antibody-coated target cells...
November 13, 2018: Cell
Eric Shifrut, Julia Carnevale, Victoria Tobin, Theodore L Roth, Jonathan M Woo, Christina T Bui, P Jonathan Li, Morgan E Diolaiti, Alan Ashworth, Alexander Marson
Human T cells are central effectors of immunity and cancer immunotherapy. CRISPR-based functional studies in T cells could prioritize novel targets for drug development and improve the design of genetically reprogrammed cell-based therapies. However, large-scale CRISPR screens have been challenging in primary human cells. We developed a new method, single guide RNA (sgRNA) lentiviral infection with Cas9 protein electroporation (SLICE), to identify regulators of stimulation responses in primary human T cells...
November 13, 2018: Cell
Daniel Arango, David Sturgill, Najwa Alhusaini, Allissa A Dillman, Thomas J Sweet, Gavin Hanson, Masaki Hosogane, Wilson R Sinclair, Kyster K Nanan, Mariana D Mandler, Stephen D Fox, Thomas T Zengeya, Thorkell Andresson, Jordan L Meier, Jeffery Coller, Shalini Oberdoerffer
Generation of the "epitranscriptome" through post-transcriptional ribonucleoside modification embeds a layer of regulatory complexity into RNA structure and function. Here, we describe N4-acetylcytidine (ac4C) as an mRNA modification that is catalyzed by the acetyltransferase NAT10. Transcriptome-wide mapping of ac4C revealed discretely acetylated regions that were enriched within coding sequences. Ablation of NAT10 reduced ac4C detection at the mapped mRNA sites and was globally associated with target mRNA downregulation...
November 12, 2018: Cell
Benjamin J Schmiedel, Divya Singh, Ariel Madrigal, Alan G Valdovino-Gonzalez, Brandie M White, Jose Zapardiel-Gonzalo, Brendan Ha, Gokmen Altay, Jason A Greenbaum, Graham McVicker, Grégory Seumois, Anjana Rao, Mitchell Kronenberg, Bjoern Peters, Pandurangan Vijayanand
While many genetic variants have been associated with risk for human diseases, how these variants affect gene expression in various cell types remains largely unknown. To address this gap, the DICE (database of immune cell expression, expression quantitative trait loci [eQTLs], and epigenomics) project was established. Considering all human immune cell types and conditions studied, we identified cis-eQTLs for a total of 12,254 unique genes, which represent 61% of all protein-coding genes expressed in these cell types...
November 8, 2018: Cell
Yongguo Li, Katharina Schnabl, Sarah-Madeleine Gabler, Monja Willershäuser, Josefine Reber, Angelos Karlas, Sanna Laurila, Minna Lahesmaa, Mueez U Din, Andrea Bast-Habersbrunner, Kirsi A Virtanen, Tobias Fromme, Florian Bolze, Libbey S O'Farrell, Jorge Alsina-Fernandez, Tamer Coskun, Vasilis Ntziachristos, Pirjo Nuutila, Martin Klingenspor
The molecular mediator and functional significance of meal-associated brown fat (BAT) thermogenesis remains elusive. Here, we identified the gut hormone secretin as a non-sympathetic BAT activator mediating prandial thermogenesis, which consequentially induces satiation, thereby establishing a gut-secretin-BAT-brain axis in mammals with a physiological role of prandial thermogenesis in the control of satiation. Mechanistically, meal-associated rise in circulating secretin activates BAT thermogenesis by stimulating lipolysis upon binding to secretin receptors in brown adipocytes, which is sensed in the brain and promotes satiation...
November 8, 2018: Cell
Ann Boija, Isaac A Klein, Benjamin R Sabari, Alessandra Dall'Agnese, Eliot L Coffey, Alicia V Zamudio, Charles H Li, Krishna Shrinivas, John C Manteiga, Nancy M Hannett, Brian J Abraham, Lena K Afeyan, Yang E Guo, Jenna K Rimel, Charli B Fant, Jurian Schuijers, Tong Ihn Lee, Dylan J Taatjes, Richard A Young
Gene expression is controlled by transcription factors (TFs) that consist of DNA-binding domains (DBDs) and activation domains (ADs). The DBDs have been well characterized, but little is known about the mechanisms by which ADs effect gene activation. Here, we report that diverse ADs form phase-separated condensates with the Mediator coactivator. For the OCT4 and GCN4 TFs, we show that the ability to form phase-separated droplets with Mediator in vitro and the ability to activate genes in vivo are dependent on the same amino acid residues...
November 8, 2018: Cell
Xing-Xing Shen, Dana A Opulente, Jacek Kominek, Xiaofan Zhou, Jacob L Steenwyk, Kelly V Buh, Max A B Haase, Jennifer H Wisecaver, Mingshuang Wang, Drew T Doering, James T Boudouris, Rachel M Schneider, Quinn K Langdon, Moriya Ohkuma, Rikiya Endoh, Masako Takashima, Ri-Ichiroh Manabe, Neža Čadež, Diego Libkind, Carlos A Rosa, Jeremy DeVirgilio, Amanda Beth Hulfachor, Marizeth Groenewald, Cletus P Kurtzman, Chris Todd Hittinger, Antonis Rokas
Budding yeasts (subphylum Saccharomycotina) are found in every biome and are as genetically diverse as plants or animals. To understand budding yeast evolution, we analyzed the genomes of 332 yeast species, including 220 newly sequenced ones, which represent nearly one-third of all known budding yeast diversity. Here, we establish a robust genus-level phylogeny comprising 12 major clades, infer the timescale of diversification from the Devonian period to the present, quantify horizontal gene transfer (HGT), and reconstruct the evolution of 45 metabolic traits and the metabolic toolkit of the budding yeast common ancestor (BYCA)...
November 8, 2018: Cell
Nadine van Montfoort, Linda Borst, Michael J Korrer, Marjolein Sluijter, Koen A Marijt, Saskia J Santegoets, Vanessa J van Ham, Ilina Ehsan, Pornpimol Charoentong, Pascale André, Nicolai Wagtmann, Marij J P Welters, Young J Kim, Sytse J Piersma, Sjoerd H van der Burg, Thorbald van Hall
Tumor-infiltrating CD8 T cells were found to frequently express the inhibitory receptor NKG2A, particularly in immune-reactive environments and after therapeutic cancer vaccination. High-dimensional cluster analysis demonstrated that NKG2A marks a unique immune effector subset preferentially co-expressing the tissue-resident CD103 molecule, but not immune checkpoint inhibitors. To examine whether NKG2A represented an adaptive resistance mechanism to cancer vaccination, we blocked the receptor with an antibody and knocked out its ligand Qa-1b , the conserved ortholog of HLA-E, in four mouse tumor models...
November 7, 2018: Cell
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