In response to growth signals, mechanistic target of rapamycin complex 1 (mTORC1) stimulates anabolic processes underlying cell growth. We found that mTORC1 increases metabolic flux through the de novo purine synthesis pathway in various mouse and human cells, thereby influencing the nucleotide pool available for nucleic acid synthesis. mTORC1 had transcriptional effects on multiple enzymes contributing to purine synthesis, with expression of the mitochondrial tetrahydrofolate (mTHF) cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) being closely associated with mTORC1 signaling in both normal and cancer cells. MTHFD2 expression and purine synthesis were stimulated by activating transcription factor 4 (ATF4), which was activated by mTORC1 independent of its canonical induction downstream of eukaryotic initiation factor 2α eIF2α phosphorylation. Thus, mTORC1 stimulates the mTHF cycle, which contributes one-carbon units to enhance production of purine nucleotides in response to growth signals.
Authors: Issam Ben-Sahra, Gerta Hoxhaj, Stéphane J. H. Ricoult, John M. Asara, Brendan D. Manning
Purine biosynthetic enzymes organize into dynamic cellular bodies called purinosomes. Little is known about the spatiotemporal control of these structures. Using super-resolution microscopy, we demonstrated that purinosomes colocalized with mitochondria, and these results were supported by isolation of purinosome enzymes with mitochondria. Moreover, the number of purinosome-containing cells responded to dysregulation of mitochondrial function and metabolism. To explore the role of intracellular signaling, we performed a kinome screen using a label-free assay and found that mechanistic target of rapamycin (mTOR) influenced purinosome assembly. mTOR inhibition reduced purinosome-mitochondria colocalization and suppressed purinosome formation stimulated by mitochondria dysregulation. Collectively, our data suggest an mTOR-mediated link between purinosomes and mitochondria, and a general means by which mTOR regulates nucleotide metabolism by spatiotemporal control over protein association.
Authors: Jarrod B. French, Sara A. Jones, Huayun Deng, Anthony M. Pedley, Doory Kim, Chung Yu Chan, Haibei Hu, Raymond J. Pugh, Hong Zhao, Youxin Zhang, Tony Jun Huang, Ye Fang, Xiaowei Zhuang, Stephen J. Benkovic
Many modern human genomes retain DNA inherited from interbreeding with archaic hominins, such as Neandertals, yet the influence of this admixture on human traits is largely unknown. We analyzed the contribution of common Neandertal variants to over 1000 electronic health record (EHR)–derived phenotypes in ~28,000 adults of European ancestry. We discovered and replicated associations of Neandertal alleles with neurological, psychiatric, immunological, and dermatological phenotypes. Neandertal alleles together explained a significant fraction of the variation in risk for depression and skin lesions resulting from sun exposure (actinic keratosis), and individual Neandertal alleles were significantly associated with specific human phenotypes, including hypercoagulation and tobacco use. Our results establish that archaic admixture influences disease risk in modern humans, provide hypotheses about the effects of hundreds of Neandertal haplotypes, and demonstrate the utility of EHR data in evolutionary analyses.
Authors: Corinne N. Simonti, Benjamin Vernot, Lisa Bastarache, Erwin Bottinger, David S. Carrell, Rex L. Chisholm, David R. Crosslin, Scott J. Hebbring, Gail P. Jarvik, Iftikhar J. Kullo, Rongling Li, Jyotishman Pathak, Marylyn D. Ritchie, Dan M. Roden, Shefali S. Verma, Gerard Tromp, Jeffrey D. Prato, William S. Bush, Joshua M. Akey, Joshua C. Denny, John A. Capra
The 2016 Gordon Research Conference schedule was published on pages 742 to 770 of this issue of the print version of Science. The current schedule can also be found online at www.grc.org/.
A weekly roundup of information on newly offered instrumentation, apparatus, and laboratory materials of potential interest to researchers.
Authors: Hong Yang, Xianjin Huang, Julian R. Thompson, Ryan M. Bright, Rasmus Astrup
Authors: Aijun Lin, Yuan Pu, Weikang Qi, Xiaoliang Li, Xiujin Li, Canfa Wang, X. Jin Yang
Authors: Valter M. Azevedo-Santos, Jean R. S. Vitule, Emili García-Berthou, Fernando M. Pelicice, Daniel Simberloff
Author: Kristen L. Mueller
Author: Kristen L. Mueller
Author: Nicholas S. Wigginton
Author: Beverly A. Purnell
Author: Kristen L. Mueller
Author: Julia Fahrenkamp-Uppenbrink
Author: Beverly A. Purnell
Author: Paula A. Kiberstis
Author: Melissa McCartney
Transposable elements (TEs) are both a boon and a bane to eukaryotic organisms, depending on where they integrate into the genome and how their sequences function once integrated. We focus on two types of TEs: long interspersed elements (LINEs) and short interspersed elements (SINEs). LINEs and SINEs are retrotransposons; that is, they transpose via an RNA intermediate. We discuss how LINEs and SINEs have expanded in eukaryotic genomes and contribute to genome evolution. An emerging body of evidence indicates that LINEs and SINEs function to regulate gene expression by affecting chromatin structure, gene transcription, pre-mRNA processing, or aspects of mRNA metabolism. We also describe how adenosine-to-inosine editing influences SINE function and how ongoing retrotransposition is countered by the body’s defense mechanisms.
Authors: Reyad A. Elbarbary, Bronwyn A. Lucas, Lynne E. Maquat
Differentiated macrophages can self-renew in tissues and expand long term in culture, but the gene regulatory mechanisms that accomplish self-renewal in the differentiated state have remained unknown. Here we show that in mice, the transcription factors MafB and c-Maf repress a macrophage-specific enhancer repertoire associated with a gene network that controls self-renewal. Single-cell analysis revealed that, in vivo, proliferating resident macrophages can access this network by transient down-regulation of Maf transcription factors. The network also controls embryonic stem cell self-renewal but is associated with distinct embryonic stem cell–specific enhancers. This indicates that distinct lineage-specific enhancer platforms regulate a shared network of genes that control self-renewal potential in both stem and mature cells.
Authors: Erinn L. Soucie, Ziming Weng, Laufey Geirsdóttir, Kaaweh Molawi, Julien Maurizio, Romain Fenouil, Noushine Mossadegh-Keller, Gregory Gimenez, Laurent VanHille, Meryam Beniazza, Jeremy Favret, Carole Berruyer, Pierre Perrin, Nir Hacohen, J.-C. Andrau, Pierre Ferrier, Patrice Dubreuil, Arend Sidow, Michael H. Sieweke
Maintaining high crop yields in an environmentally sustainable manner requires the development of disease-resistant crop varieties. We describe a method to engineer disease resistance in plants by means of an endogenous disease resistance gene from Arabidopsis thaliana named RPS5, which encodes a nucleotide-binding leucine-rich repeat (NLR) protein. RPS5 is normally activated when a second host protein, PBS1, is cleaved by the pathogen-secreted protease AvrPphB. We show that the AvrPphB cleavage site within PBS1 can be substituted with cleavage sites for other pathogen proteases, which then enables RPS5 to be activated by these proteases, thereby conferring resistance to new pathogens. This “decoy” approach may be applicable to other NLR proteins and should enable engineering of resistance in plants to diseases for which we currently lack robust genetic resistance.
Authors: Sang Hee Kim, Dong Qi, Tom Ashfield, Matthew Helm, Roger W. Innes
The lung is constantly exposed to environmental atmospheric cues. How it senses and responds to these cues is poorly defined. Here, we show that Roundabout receptor (Robo) genes are expressed in pulmonary neuroendocrine cells (PNECs), a rare, innervated epithelial population. Robo inactivation in mouse lung results in an inability of PNECs to cluster into sensory organoids and triggers increased neuropeptide production upon exposure to air. Excess neuropeptides lead to an increase in immune infiltrates, which in turn remodel the matrix and irreversibly simplify the alveoli. We demonstrate in vivo that PNECs act as precise airway sensors that elicit immune responses via neuropeptides. These findings suggest that the PNEC and neuropeptide abnormalities documented in a wide array of pulmonary diseases may profoundly affect symptoms and progression.
Authors: Kelsey Branchfield, Leah Nantie, Jamie M. Verheyden, Pengfei Sui, Mark D. Wienhold, Xin Sun
T cell–mediated destruction of insulin-producing β cells in the pancreas causes type 1 diabetes (T1D). CD4 T cell responses play a central role in β cell destruction, but the identity of the epitopes recognized by pathogenic CD4 T cells remains unknown. We found that diabetes-inducing CD4 T cell clones isolated from nonobese diabetic mice recognize epitopes formed by covalent cross-linking of proinsulin peptides to other peptides present in β cell secretory granules. These hybrid insulin peptides (HIPs) are antigenic for CD4 T cells and can be detected by mass spectrometry in β cells. CD4 T cells from the residual pancreatic islets of two organ donors who had T1D also recognize HIPs. Autoreactive T cells targeting hybrid peptides may explain how immune tolerance is broken in T1D.
Authors: Thomas Delong, Timothy A. Wiles, Rocky L. Baker, Brenda Bradley, Gene Barbour, Richard Reisdorph, Michael Armstrong, Roger L. Powell, Nichole Reisdorph, Nitesh Kumar, Colleen M. Elso, Megan DeNicola, Rita Bottino, Alvin C. Powers, David M. Harlan, Sally C. Kent, Stuart I. Mannering, Kathryn Haskins
Major histocompatibility complex E (MHC-E) is a highly conserved, ubiquitously expressed, nonclassical MHC class Ib molecule with limited polymorphism that is primarily involved in the regulation of natural killer (NK) cells. We found that vaccinating rhesus macaques with rhesus cytomegalovirus vectors in which genes Rh157.5 and Rh157.4 are deleted results in MHC-E–restricted presentation of highly varied peptide epitopes to CD8αβ+ T cells, at ~4 distinct epitopes per 100 amino acids in all tested antigens. Computational structural analysis revealed that MHC-E provides heterogeneous chemical environments for diverse side-chain interactions within a stable, open binding groove. Because MHC-E is up-regulated to evade NK cell activity in cells infected with HIV, simian immunodeficiency virus, and other persistent viruses, MHC-E–restricted CD8+ T cell responses have the potential to exploit pathogen immune-evasion adaptations, a capability that might endow these unconventional responses with superior efficacy.
Authors: Scott G. Hansen, Helen L. Wu, Benjamin J. Burwitz, Colette M. Hughes, Katherine B. Hammond, Abigail B. Ventura, Jason S. Reed, Roxanne M. Gilbride, Emily Ainslie, David W. Morrow, Julia C. Ford, Andrea N. Selseth, Reesab Pathak, Daniel Malouli, Alfred W. Legasse, Michael K. Axthelm, Jay A. Nelson, Geraldine M. Gillespie, Lucy C. Walters, Simon Brackenridge, Hannah R. Sharpe, César A. López, Klaus Früh, Bette T. Korber, Andrew J. McMichael, S. Gnanakaran, Jonah B. Sacha, Louis J. Picker
Chromatin regulators play a major role in establishing and maintaining gene expression states. Yet how they control gene expression in single cells, quantitatively and over time, remains unclear. We used time-lapse microscopy to analyze the dynamic effects of four silencers associated with diverse modifications: DNA methylation, histone deacetylation, and histone methylation. For all regulators, silencing and reactivation occurred in all-or-none events, enabling the regulators to modulate the fraction of cells silenced rather than the amount of gene expression. These dynamics could be described by a three-state model involving stochastic transitions between active, reversibly silent, and irreversibly silent states. Through their individual transition rates, these regulators operate over different time scales and generate distinct types of epigenetic memory. Our results provide a framework for understanding and engineering mammalian chromatin regulation and epigenetic memory.
Authors: Lacramioara Bintu, John Yong, Yaron E. Antebi, Kayla McCue, Yasuhiro Kazuki, Narumi Uno, Mitsuo Oshimura, Michael B. Elowitz
Monoubiquitinated histone H2B plays multiple roles in transcription activation. H2B is deubiquitinated by the Spt-Ada-Gcn5 acetyltransferase (SAGA) coactivator, which contains a four-protein subcomplex known as the deubiquitinating (DUB) module. The crystal structure of the Ubp8/Sgf11/Sus1/Sgf73 DUB module bound to a ubiquitinated nucleosome reveals that the DUB module primarily contacts H2A/H2B, with an arginine cluster on the Sgf11 zinc finger domain docking on the conserved H2A/H2B acidic patch. The Ubp8 catalytic domain mediates additional contacts with H2B, as well as with the conjugated ubiquitin. We find that the DUB module deubiquitinates H2B both in the context of the nucleosome and in H2A/H2B dimers complexed with the histone chaperone, FACT, suggesting that SAGA could target H2B at multiple stages of nucleosome disassembly and reassembly during transcription.
Authors: Michael T. Morgan, Mahmood Haj-Yahya, Alison E. Ringel, Prasanthi Bandi, Ashraf Brik, Cynthia Wolberger
When modern humans met and mated with Neandertals about 50,000 years ago, they picked up genes that are shaping health and well-being today. In a new study on p. 737, researchers use a powerful new method for scanning the electronic health records of 28,000 Americans to show that some Neandertal gene variants today may boost the risk of depression, skin lesions, blood clots, and other disorders. The work reveals a dozen Neandertal genes likely to cause significant risk of disease today. Neandertal genes aren't all bad. Two other new studies identified three archaic genes that boost immune response. And most archaic genes that persist in humans were likely beneficial in prehistoric times. But some now cause disease because modern lifestyles and environments are so different. For example, a gene variant that makes blood clot faster might have been life-saving in prehistory, when people hunted dangerous animals and mostly died young. But today that variant boosts the risk of stroke.
Author: Ann Gibbons
Every year, chemists invent thousands of new chemicals, and many ultimately find their way into global use. Predicting which ones will pose health or environmental hazards, however, has proven difficult. This week, a group of researchers unveiled a tool that could help streamline the process: a vast database of safety information that will allow users to compare new chemicals to existing compounds with similar structures, and flag potential risks. "You could imagine that, before even synthesizing [a chemical], a chemist puts the structure into the [tool] to ask if it's safe," says toxicologist Thomas Hartung of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, who led the effort. To create the screening tool, the researchers dug deep into a "gold mine" of data on 9800 compounds collected by the European Chemicals Agency. But experts caution that structural similarities, although promising, are just one piece of the puzzle in assessing a compound's safety.
Author: Tania Rabesandratana
In anoxic marine sediments, consortia of methane-consuming archaea and sulfate-reducing bacteria oxidize methane. Together, they thereby control methane discharge in a metabolism of global importance. During this cooperative interspecies interaction, known as syntrophy, the excess reducing equivalents released by one species feed the second species (see the first figure). The two species only gain energy when they work together. On page 703 of this issue, Scheller et al. (1) show that these partners can be decoupled in the laboratory. The results help to elucidate the molecular mechanisms that control methane discharge in marine systems.
Authors: Amelia-Elena Rotaru, Bo Thamdrup
Mitochondria and plastids are essential for harnessing energy in eukaryotic cells. They are believed to have formed through primary endosymbioses, in which bacterial symbionts were converted into energy-producing organelles. Primary endosymbiosis is extremely rare: Only one other case is known, in the amoeba Paulinella (1). This rarity is usually attributed to the many innovations that are required for organelles to be integrated into the cellular machinery (2). However, the first challenges for an endosymbiont are to avoid being digested by the host and to replicate in its novel environment. Recent studies provide clues to how the precursors to mitochondria and the plastid overcame these challenges.
Authors: Steven G. Ball, Debashish Bhattacharya, Andreas P. M. Weber
Expression of the genome is controlled by an intricate “web” of proteins, chemical modifications, and RNA that together organize genomic DNA into chromatin. Molecular studies of the various forms and levels of chromatin organization are advancing rapidly, revealing an increasing number of connections between chromatin and cellular and disease processes, as well as a fast-expanding web of known chromatin factors (1). On page 720, Bintu et al. take a radically different approach to dissecting chromatin, focusing not on molecular but on “algorithmic” chromatin biology (2). By studying how individual chromatin regulators (CRs) operate to produce distinct gene expression outputs within individual cells, they find that chromatin's complexity can be reduced into an elegant and unifying model of gene regulation.
Authors: Albert J. Keung, Ahmad S. Khalil
The human respiratory tract transports millions of liters of gases throughout life. Because the conducting airways are exposed to countless microbes, particles, and toxicants, the tract has evolved an immune system that protects lung structure and function (1). Ventilation is primarily controlled by neuromuscular activity in the diaphragm and other muscles, and by sensory inputs from relatively rare pulmonary neuroepithelial cells. These cells cluster and form neuroepithelial bodies (NEBs) at branch points along the lung's airways. On page 707 of this issue, Branchfield et al. (2) reveal how NEBs arise during lung morphogenesis and clarify how their role in inflammation and tissue remodeling is relevant to the pathogenesis of chronic lung diseases that affect children.
Authors: Jeffrey A. Whitsett, Edward E. Morrisey
Although more than 95% of active climate scientists attribute recent global warming to human causes (1, 2) and most of the general public accepts that climate change is occurring, only about half of U.S. adults believe that human activity is the predominant cause (3), which is the lowest among 20 nations polled in 2014 (4). We examine how this societal debate affects science classrooms and find that, whereas most U.S. science teachers include climate science in their courses, their insufficient grasp of the science may hinder effective teaching. Mirroring some actors in the societal debate over climate change, many teachers repeat scientifically unsupported claims in class. Greater attention to teachers' knowledge, but also values, is critical.
Authors: Eric Plutzer, Mark McCaffrey, A. Lee Hannah, Joshua Rosenau, Minda Berbeco, Ann H. Reid
To participate in the choreography of signals that occur on the chromosome during gene activation, many multisubunit chromatin-modifying complexes contain more than one enzyme that chemically alter histones, the protein constituent of chromatin. These complexes themselves often contain modules or clusters of subunits dedicated to specific functions of the complex (1). The Spt-Ada-Gcn5 acetyltransferase (SAGA) complex is a good example of this organization. It is highly conserved from yeast to humans, contains up to 20 subunits, and is about 2 MDa in size. SAGA contains several functional modules, two of which have enzymatic activities and others that mediate SAGA interactions with proteins that control transcription (2). Hence, teamwork between these modules is crucial for the steps leading to transcription initiation and its transition to RNA elongation (3). Even within each module, teamwork between individual subunits is necessary to promote accurate enzymatic activity. On page 725 in this issue, Morgan et al. (4) provide structural and biochemical data that nicely illustrate cooperation between subunits within the module that contains a histone deubiquitinase, and between this module and the remainder of the SAGA complex.
Author: Jerry L. Workman
Mitochondria are organelles found in nearly all cells in the human body and are best known for their role in regulating cellular energy balance (sometimes described as the “energy factory” of the cell). Mitochondrial DNA (mtDNA) is the only source of DNA in human cells found outside of the nucleus. The mitochondrial genome contains 37 genes (as compared with the 20,000 to 30,000 found in the nuclear genome), but pathogenic mutations in mtDNA can lead to rare, serious diseases that tend to affect organs with the highest energy demand and can be severely debilitating, progressive, and sometimes fatal in childhood (1, 2). mtDNA diseases involve extensive clinical and genetic heterogeneity, creating a challenge for estimates of prevalence. Estimates range from 1 in 200 (3) to 1 in 5000 (4) people harboring a pathogenic mtDNA mutation that may result in disease.
Authors: Anne B. Claiborne, Rebecca A. English, Jeffrey P. Kahn
Proliferating cells must coordinate their metabolic activities to meet the bioenergetic and biosynthetic demands of anabolic growth. Rapidly growing cells—such as cancer cells—achieve this in part by rewiring their metabolic pathways to increase flux through specific biosynthetic pathways. A more complex issue is how metabolic enzymes are organized to ensure efficient processing of metabolic intermediates. On pages 728 and 733 of this issue, Ben-Sahra et al. (1) and French et al. (2), reveal how a protein complex called mammalian/mechanistic target of rapamycin complex 1 (mTORC1) orchestrates metabolism and purine nucleotide biosynthesis to promote cell proliferation.
Authors: Eric H. Ma, Russell G. Jones
Gone are the days when microbes were considered mere disease-spreading agents that must be purged at all costs. Through a combination of videos, larger-than-life models, interactive displays, and live performance, The Secret World Inside You shows how microbes engage in complex, and often mutually beneficial, interactions with our skin, immune, and digestive systems.
Author: Valerie Thompson
By now, the tragic saga of the lead-contaminated drinking water in Flint, Michigan, is well known. Unlike some disasters, this one was not inevitable, and there were many warning signs that could have halted it much sooner. In the developed world, citizens have come to trust that basic public services such as water, power, and sanitation will be provided, for a fee, safely and reliably. Therefore, Flint is not just a nightmare for its 100,000 residents, because it causes all citizens to question whether public officials, who are entrusted with providing essential services, have health and welfare in mind. With criminal investigation of the Flint crisis now under way, my focus is not on assigning blame but on how to prevent a tragedy like this from happening again.
Author: Marcia McNutt
In science news around the world, U.S. President Barack Obama releases the final budget request of his tenure, a preliminary report by French authorities finds fault with how a company handled a clinical trial crisis last month that resulted in one death, a Chinese firm bids for genetically modified crops giant Syngenta, a Nobel official resigns in the wake of a widening scandal around famed surgeon Paolo Macchiarini, a French research agency accused of "biopiracy" has agreed to share profits from a potential malaria drug with indigenous peoples who helped identify its plant source, and more. Also, the Howard Hughes Medical Institute and Stanford University each are slated to have new presidents later this year. And a 6th century cold spell, now identified from tree rings, may have helped trigger societal upheaval at the time, leading to widespread crop failures, migrations, and possibly abetting the spread of plague.
