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Cell 2018 Dec;175(7):1991

Cell 2018 Dec;175(7):1989-1990

Cell 2018 Dec;175(7):1972-1988.e16

Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

In vitro cancer cultures, including three-dimensional organoids, typically contain exclusively neoplastic epithelium but require artificial reconstitution to recapitulate the tumor microenvironment (TME). The co-culture of primary tumor epithelia with endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has been particularly elusive. Here, an air-liquid interface (ALI) method propagated patient-derived organoids (PDOs) from >100 human biopsies or mouse tumors in syngeneic immunocompetent hosts as tumor epithelia with native embedded immune cells (T, B, NK, macrophages). Read More

Cell 2018 Dec;175(7):1931-1945.e18

Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA; The J. David Gladstone Institutes, San Francisco, CA, USA. Electronic address:

Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems-level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provides information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Read More

Cell 2018 Dec;175(7):1917-1930.e13

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA. Electronic address:

Ebola virus (EBOV) infection often results in fatal illness in humans, yet little is known about how EBOV usurps host pathways during infection. To address this, we used affinity tag-purification mass spectrometry (AP-MS) to generate an EBOV-host protein-protein interaction (PPI) map. We uncovered 194 high-confidence EBOV-human PPIs, including one between the viral transcription regulator VP30 and the host ubiquitin ligase RBBP6. Read More

Cell 2018 Dec;175(7):1902-1916.e13

Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. Electronic address:

Nuclear architecture has never been carefully examined during early mammalian development at the stages leading to establishment of the embryonic and extra-embryonic lineages. Heterogeneous activity of the methyltransferase CARM1 during these stages results in differential methylation of histone H3R26 to modulate establishment of these two lineages. Here we show that CARM1 accumulates in nuclear granules at the 2- to 4-cell stage transition in the mouse embryo, with the majority corresponding to paraspeckles. Read More

Cell 2018 Dec;175(7):1887-1901.e18

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China; University of Chinese Academy of Sciences, 100049 Beijing, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101 Beijing, China. Electronic address:

In early mammalian embryos, it remains unclear how the first cell fate bias is initially triggered and amplified toward cell fate segregation. Here, we report that a long noncoding RNA, LincGET, is transiently and asymmetrically expressed in the nucleus of two- to four-cell mouse embryos. Overexpression of LincGET in one of the two-cell blastomeres biases its progeny predominantly toward the inner cell mass (ICM) fate. Read More

Cell 2018 Dec;175(7):1827-1841.e17

Howard Hughes Medical Institute, Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address:

Newborn mice emit signals that promote parenting from mothers and fathers but trigger aggressive responses from virgin males. Although pup-directed attacks by males require vomeronasal function, the specific infant cues that elicit this behavior are unknown. We developed a behavioral paradigm based on reconstituted pup cues and showed that discrete infant morphological features combined with salivary chemosignals elicit robust male aggression. Read More

Cell 2018 Dec;175(7):1756-1768.e17

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard University Medical School, Boston, MA 02115, USA. Electronic address:

Irisin is secreted by muscle, increases with exercise, and mediates certain favorable effects of physical activity. In particular, irisin has been shown to have beneficial effects in adipose tissues, brain, and bone. However, the skeletal response to exercise is less clear, and the receptor for irisin has not been identified. Read More

Cell 2018 Dec;175(7):1728-1729

Department of Integrative Structural and Computational Biology, the Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address:

Viruses use mimicry to hijack cellular machinery, but can human cells use mimicry as an antiviral approach? Batra et al. identify a novel antiviral restriction factor, RBBP6, by characterizing the cellular interactome of Ebola virus. RBBP6 targets the Ebola virus transcription factor VP30 by mimicking the binding of Ebola virus nucleoprotein. Read More

Cell 2018 Dec;175(7):1725-1727

Cancer Research Center and Wohl Institute for Translational Medicine, Chaim Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address:

Arango et al. expand the repertoire of epitranscriptomic modifications by identifying N-acetylcytidine in mRNA catalyzed by the known dual acetyltransferase NAT10. It occurs mainly in the coding sequence, likely in wobble positions of select codons, where it promotes stability and translation, possibly by safeguarding cognate codon-anticodon interaction. Read More

Cell 2018 Dec;175(7):1723-1725

Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Electronic address:

New findings suggest that transcription enhancers work by recruitment of a large dynamic network of coactivators and other factors responsible for gene activation. Formation of these condensates is driven by DNA-bound transcription factors, their intrinsically disordered activation domains, and dynamic low-specificity interactions within the complex. Read More

Cell 2018 Dec;175(7):1720-1722

MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, UK.

One of the major breakthroughs of cancer immunotherapy has come from blocking immune checkpoint molecules on tumor-reactive T cells. Now, two studies examine targeting of a novel immune checkpoint, NKG2A, that can be expressed on both NK cells and on CD8 T cells, either combined with a tumor-targeting antibody or with a tumor-specific vaccine. Read More

Cell 2018 Dec;175(7):1719

Department of Medicine, University Hospital, Lund, Sweden. Electronic address:

Monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (CLR + RAMP1) offer considerable improvements over existing drugs in migraine prophylaxis and are the first designed to act on the trigeminal pain system. Erenumab is approved by the FDA and EMA and has reached the market since May 2018. Two antibodies, fremanezumab and galcanezumab, directed towards the CGRP ligand, were approved by the FDA in September 2018. Read More

Cell 2018 Nov 29. Epub 2018 Nov 29.

Biological Design Center, Boston University, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA. Electronic address:

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. Read More

Cell 2018 Dec 1. Epub 2018 Dec 1.

German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg, Germany; Heidelberg University, Medical Faculty, Im Neuenheimer Feld 672, Heidelberg, Germany. Electronic address:

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. Read More

Cell 2018 Dec 6;175(7):1796-1810.e20. Epub 2018 Dec 6.

Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address:

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. Read More

Cell 2018 Dec 5. Epub 2018 Dec 5.

Department of Bio and Health Informatics, Technical University of Denmark, Kemitorvet 208, 2800 Kongens Lyngby, Denmark. Electronic address:

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. Read More

Cell 2018 Nov 13. Epub 2018 Nov 13.

Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA 94305, USA; Department of Pathology, Stanford University, Palo Alto, CA 94305, USA; Department of Pediatrics, Stanford University, Palo Alto, CA 94305, USA; Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94305, USA. Electronic address:

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. Read More

Cell 2018 Dec 29;175(7):1731-1743.e13. Epub 2018 Nov 29.

Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France; Aix Marseille Université, INSERM, CNRS, Centre d'Immunologie de Marseille-Luminy, 13009 Marseille, France; Service d'Immunologie, Marseille Immunopole, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, 13005 Marseille, France. Electronic address:

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. Read More

Cell 2018 Nov 27. Epub 2018 Nov 27.

Institute for Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK. Electronic address:

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. Read More

Cell 2018 Nov 27. Epub 2018 Nov 27.

Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

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. Read More

Cell 2018 Nov 26. Epub 2018 Nov 26.

Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101 Beijing, China; University of Chinese Academy of Sciences, 100049 Beijing, China; State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China. Electronic address:

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. Read More

Cell 2018 Nov 29. Epub 2018 Nov 29.

Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA; University of California, Berkeley/University of California, San Francisco Graduate Group in Bioengineering, Berkeley, CA 94720, USA; Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address:

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. Read More

Cell 2018 Dec 29;175(7):1744-1755.e15. Epub 2018 Nov 29.

Department of Medical Oncology, Leiden University Medical Center, 2333 ZA, Leiden, the Netherlands. Electronic address:

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-1, the conserved ortholog of HLA-E, in four mouse tumor models. Read More

Cell 2018 Dec 29;175(7):1811-1826.e21. Epub 2018 Nov 29.

Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA.

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. Read More

Cell 2018 Nov 20. Epub 2018 Nov 20.

Molecular Pharmacology, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.

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. Read More

Cell 2018 Dec 29;175(7):1856-1871.e21. Epub 2018 Nov 29.

Structural Molecular Biology Group, Novo Nordisk Foundation Centre for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark. Electronic address:

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. Read More

Cell 2018 Nov;175(6):1717

Cell 2018 Nov;175(6):1716

Cell 2018 Nov;175(6):1607-1619.e15

Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

In the healthy adult liver, most hepatocytes proliferate minimally. However, upon physical or chemical injury to the liver, hepatocytes proliferate extensively in vivo under the direction of multiple extracellular cues, including Wnt and pro-inflammatory signals. Currently, liver organoids can be generated readily in vitro from bile-duct epithelial cells, but not hepatocytes. Read More

Cell 2018 Nov;175(6):1591-1606.e19

Oncode Institute, Hubrecht Institute, KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, the Netherlands; University Medical Center Utrecht, Cancer Genomics Netherlands, 3584CX Utrecht, the Netherlands; The Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands. Electronic address:

The mammalian liver possesses a remarkable regenerative ability. Two modes of damage response have been described: (1) The "oval cell" response emanates from the biliary tree when all hepatocytes are affected by chronic liver disease. (2) A massive, proliferative response of mature hepatocytes occurs upon acute liver damage such as partial hepatectomy (PHx). Read More

Cell 2018 Nov;175(6):1546-1560.e17

Department of Medicine, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address:

Mammalian folate metabolism is comprised of cytosolic and mitochondrial pathways with nearly identical core reactions, yet the functional advantages of such an organization are not well understood. Using genome-editing and biochemical approaches, we find that ablating folate metabolism in the mitochondria of mammalian cell lines results in folate degradation in the cytosol. Mechanistically, we show that QDPR, an enzyme in tetrahydrobiopterin metabolism, moonlights to repair oxidative damage to tetrahydrofolate (THF). Read More

Cell 2018 Nov;175(6):1520-1532.e15

Vollum Institute, Oregon Health and Science University, Portland, OR 97239, USA; Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR 97239, USA; Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR 97239, USA. Electronic address:

N-methyl-D-aspartate receptors (NMDARs) play essential roles in memory formation, neuronal plasticity, and brain development, with their dysfunction linked to a range of disorders from ischemia to schizophrenia. Zinc and pH are physiological allosteric modulators of NMDARs, with GluN2A-containing receptors inhibited by nanomolar concentrations of divalent zinc and by excursions to low pH. Despite the widespread importance of zinc and proton modulation of NMDARs, the molecular mechanism by which these ions modulate receptor activity has proven elusive. Read More

Cell 2018 Nov;175(6):1481-1491.e13

Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Howard Hughes Medical Institute, Princeton University, Princeton, NJ 08544, USA. Electronic address:

Phase transitions involving biomolecular liquids are a fundamental mechanism underlying intracellular organization. In the cell nucleus, liquid-liquid phase separation of intrinsically disordered proteins (IDPs) is implicated in assembly of the nucleolus, as well as transcriptional clusters, and other nuclear bodies. However, it remains unclear whether and how physical forces associated with nucleation, growth, and wetting of liquid condensates can directly restructure chromatin. Read More

Cell 2018 Nov;175(6):1467-1480.e13

Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA; Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Howard Hughes Medical Institute, Princeton University, Princeton, NJ 08544, USA. Electronic address:

Liquid-liquid phase separation plays a key role in the assembly of diverse intracellular structures. However, the biophysical principles by which phase separation can be precisely localized within subregions of the cell are still largely unclear, particularly for low-abundance proteins. Here, we introduce an oligomerizing biomimetic system, "Corelets," and utilize its rapid and quantitative light-controlled tunability to map full intracellular phase diagrams, which dictate the concentrations at which phase separation occurs and the transition mechanism, in a protein sequence dependent manner. Read More

Cell 2018 Nov;175(6):1463-1465

Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.

Trained innate immunity mediates protection against heterologous infections and is mediated by epigenetic and functional reprogramming of myeloid cells and their progenitors. Now, Yao et al. describe trained immunity induced locally in alveolar macrophages by a viral infection, with IFNγ release from effector CD8 lymphocytes initiating this process. Read More

Cell 2018 Nov;175(6):1461-1463

Departments of Dermatology and Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Mechanisms underlying aging of the skin dermis are poorly understood. Now, two studies (Marsh et al., 2018; Salzer et al. Read More

Cell 2018 Nov;175(6):1459-1460

Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA. Electronic address:

Most theories of meal-induced thermogenesis involve a gut-brain-brown adipose tissue axis driving sympathetic nervous system-mediated thermogenesis. Li et al. demonstrate that secretin released by the gut after a meal binds to abundant receptors in brown adipose tissue to stimulate thermogenesis, inhibiting food intake and thereby suggesting a novel role for secretin regulating satiety. Read More

Cell 2018 Nov;175(6):1457-1459

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; Cavendish Laboratory, University of Cambridge, J J Thomson Avenue, Cambridge CB3 0HE, UK. Electronic address:

The use of optogenetic approaches has revealed new roles for intracellular protein condensates described in two papers in this issue of Cell (Bracha et. al., 2018; Shin et al. Read More

Cell 2018 Nov;175(6):1452-1454

Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY 10065, USA. Electronic address:

The 2018 Nobel Prize in Medicine and Physiology has been awarded to James P. Allison and Tasuku Honjo for their discovery of cancer therapy by inhibition of negative immune regulation. These insights have given rise to a class of medicines that have now entered routine use in the treatment of advanced cancers and have provided a foundation for additional exploration and discovery of pathways critical to modulating the immune response to cancer. Read More

Cell 2018 Nov;175(6):1449-1451

Center for Physics of Evolving Systems, Department of Biochemistry & Molecular Biology, The Institute for Molecular Engineering, University of Chicago, Chicago, IL 60637, USA. Electronic address:

This year, the Nobel Prize in Chemistry was awarded to three pioneering scientists who applied laboratory evolution for protein engineering: Frances Arnold, George P. Smith, and Sir Gregory P. Winter. Read More

Cell 2018 Nov;175(6):1445-1448

Physics Department & LASSP, Cornell University, Ithaca, NY 14853, USA; Howard Hughes Medical Institute, Cornell University, Ithaca, NY 14853, USA. Electronic address:

The 2018 Nobel Prize in Physics has been awarded jointly to Arthur Ashkin for the discovery and development of optical tweezers and their applications to biological systems and to Gérard Mourou and Donna Strickland for the invention of laser chirped pulse amplification. Here we focus on Arthur Ashkin and how his revolutionary work opened a window into the world of molecular mechanics and spurred the rise of single-molecule biophysics. Read More

Cell 2018 Nov 25;175(5):1430-1442.e17. Epub 2018 Oct 25.

National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. Electronic address:

In eukaryotic cells, organelles and the cytoskeleton undergo highly dynamic yet organized interactions capable of orchestrating complex cellular functions. Visualizing these interactions requires noninvasive, long-duration imaging of the intracellular environment at high spatiotemporal resolution and low background. To achieve these normally opposing goals, we developed grazing incidence structured illumination microscopy (GI-SIM) that is capable of imaging dynamic events near the basal cell cortex at 97-nm resolution and 266 frames/s over thousands of time points. Read More

Cell 2018 Nov 25;175(5):1418-1429.e9. Epub 2018 Oct 25.

Département de Biochimie, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, QC H3C 3J7, Canada; Centre Robert-Cedergren, Bio-Informatique et Génomique, Université de Montréal, C.P. 6128, Succursale centre-ville, Montréal, QC H3C 3J7, Canada. Electronic address:

We report here a simple and global strategy to map out gene functions and target pathways of drugs, toxins, or other small molecules based on "homomer dynamics" protein-fragment complementation assays (hdPCA). hdPCA measures changes in self-association (homomerization) of over 3,500 yeast proteins in yeast grown under different conditions. hdPCA complements genetic interaction measurements while eliminating the confounding effects of gene ablation. Read More

Cell 2018 Nov 25;175(5):1393-1404.e11. Epub 2018 Oct 25.

Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China; Key laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai 201210, China; Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China. Electronic address:

Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNA. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. Read More

Cell 2018 Nov 25;175(5):1289-1306.e20. Epub 2018 Oct 25.

Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. Electronic address:

Obesity is a major driver of cancer, especially hepatocellular carcinoma (HCC). The prevailing view is that non-alcoholic steatohepatitis (NASH) and fibrosis or cirrhosis are required for HCC in obesity. Here, we report that NASH and fibrosis and HCC in obesity can be dissociated. Read More

Cell 2018 Nov 25;175(5):1259-1271.e13. Epub 2018 Oct 25.

Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK. Electronic address:

Generally repressed by epigenetic mechanisms, retrotransposons represent around 40% of the murine genome. At the Agouti viable yellow (A) locus, an endogenous retrovirus (ERV) of the intracisternal A particle (IAP) class retrotransposed upstream of the agouti coat-color locus, providing an alternative promoter that is variably DNA methylated in genetically identical individuals. This results in variable expressivity of coat color that is inherited transgenerationally. Read More

Cell 2018 Nov 25;175(5):1244-1258.e26. Epub 2018 Oct 25.

Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA. Electronic address:

Cyclin-dependent kinase 9 (CDK9) promotes transcriptional elongation through RNAPII pause release. We now report that CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell drug screen with genetic confirmation, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression, cell differentiation, and activation of endogenous retrovirus genes. Read More

Cell 2018 Nov 15;175(6):1701-1715.e16. Epub 2018 Nov 15.

La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA; Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; University of Southampton, Faculty of Medicine, Southampton SO16 6YD, UK. Electronic address:

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. Read More