Search Our Scientific Publications & Authors

Cell 2019 Feb 8. Epub 2019 Feb 8.

Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

Methylation of histone H3 K79 by Dot1L is a hallmark of actively transcribed genes that depends on monoubiquitination of H2B K120 (H2B-Ub) and is an example of histone modification cross-talk that is conserved from yeast to humans. We report here cryo-EM structures of Dot1L bound to ubiquitinated nucleosome that show how H2B-Ub stimulates Dot1L activity and reveal a role for the histone H4 tail in positioning Dot1L. We find that contacts mediated by Dot1L and the H4 tail induce a conformational change in the globular core of histone H3 that reorients K79 from an inaccessible position, thus enabling this side chain to insert into the active site in a position primed for catalysis. Read More

Cell 2019 Jan 29. Epub 2019 Jan 29.

David H. Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address:

Cell size varies greatly between cell types, yet within a specific cell type and growth condition, cell size is narrowly distributed. Why maintenance of a cell-type specific cell size is important remains poorly understood. Here we show that growing budding yeast and primary mammalian cells beyond a certain size impairs gene induction, cell-cycle progression, and cell signaling. Read More

Cell 2019 Jan 31. Epub 2019 Jan 31.

Department of Molecular, Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research, University of California at Los Angeles, Los Angeles, CA 90095, USA; Howard Hughes Medical Institute, University of California at Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

The RNA-directed DNA methylation (RdDM) pathway in plants controls gene expression via cytosine DNA methylation. The ability to manipulate RdDM would shed light on the mechanisms and applications of DNA methylation to control gene expression. Here, we identified diverse RdDM proteins that are capable of targeting methylation and silencing in Arabidopsis when tethered to an artificial zinc finger (ZF-RdDM). Read More

Cell 2019 Feb 5. Epub 2019 Feb 5.

Committee on Immunology, University of Chicago, Chicago, IL, USA; Department of Medicine, University of Chicago, Chicago, IL, USA; Department of Pathology, University of Chicago, Chicago, IL, USA. Electronic address:

Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vγ4/Vδ1 intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4/Vδ1 IELs was accompanied by the expansion of gluten-sensitive, interferon-γ-producing Vδ1 IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Read More

Cell 2019 Feb;176(4):944-945

Cell 2019 Feb;176(4):869-881.e13

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

Circular RNAs (circRNAs) are an intriguing class of RNA due to their covalently closed structure, high stability, and implicated roles in gene regulation. Here, we used an exome capture RNA sequencing protocol to detect and characterize circRNAs across >2,000 cancer samples. When compared against Ribo-Zero and RNase R, capture sequencing significantly enhanced the enrichment of circRNAs and preserved accurate circular-to-linear ratios. Read More

Cell 2019 Feb;176(4):856-868.e10

Department of Physics and Astronomy, University of Pennsylvania, 209 S. 33(rd) Street, Philadelphia, PA 19104, USA. Electronic address:

The ornately geometric walls of pollen grains have inspired scientists for decades. We show that the evolved diversity of these patterns is entirely recapitulated by a biophysical model in which an initially uniform polysaccharide layer in the extracellular space, mechanically coupled to the cell membrane, phase separates to a spatially modulated state. Experiments reveal this process occurring in living cells. Read More

Cell 2019 Feb;176(4):831-843.e22

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. Electronic address:

The cancer transcriptome is remarkably complex, including low-abundance transcripts, many not polyadenylated. To fully characterize the transcriptome of localized prostate cancer, we performed ultra-deep total RNA-seq on 144 tumors with rich clinical annotation. This revealed a linear transcriptomic subtype associated with the aggressive intraductal carcinoma sub-histology and a fusion profile that differentiates localized from metastatic disease. Read More

Cell 2019 Feb;176(4):743-756.e17

Department of Neurology, University of California, San Francisco (UCSF), San Francisco, CA, USA; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, CA, USA. Electronic address:

Direct comparisons of human and non-human primate brains can reveal molecular pathways underlying remarkable specializations of the human brain. However, chimpanzee tissue is inaccessible during neocortical neurogenesis when differences in brain size first appear. To identify human-specific features of cortical development, we leveraged recent innovations that permit generating pluripotent stem cell-derived cerebral organoids from chimpanzee. Read More

Cell 2019 Feb;176(4):687-701.e5

Laboratory of Neurogenetics and Behavior, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA; Kavli Neural Systems Institute, New York, NY 10065, USA. Electronic address:

Female Aedes aegypti mosquitoes bite humans to obtain blood to develop their eggs. Remarkably, their strong attraction to humans is suppressed for days after the blood meal by an unknown mechanism. We investigated a role for neuropeptide Y (NPY)-related signaling in long-term behavioral suppression and discovered that drugs targeting human NPY receptors modulate mosquito host-seeking. Read More

Cell 2019 Feb;176(4):684-685

Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. Electronic address:

Using induced pluripotent stem cells and microelectromechanical device technology Zhao et al. have developed 'organs on chips' representing the different chambers of the heart and used them to replicate healthy and diseased tissues in vitro. These systems offer investigators and the pharmaceutical industry a new tool in testing the safety and efficacy of new medicinal therapeutics. Read More

Cell 2019 Feb;176(4):681-684

Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Division of Hematology, Department of Medicine, University of Washington, Seattle, WA 98109, USA. Electronic address:

Through dissecting the link between spatial genome organization and DNA replication timing, Sima et al. (2018) discover early replicating control elements (ERCEs), a new type of cis-acting elements that regulate replication timing, transcription, and multiple layers of three-dimensional features of genome organization. The study has important implications for unraveling control elements of high-order genome structure and function. Read More

Cell 2019 Feb;176(4):679-681

Grupo Mosquitos Vetores: Endossimbiontes e Interação Patógeno-Vetor, Instituto René Rachou, Fiocruz, Belo Horizonte, MG, Brazil. Electronic address:

New possibilities for vector-borne disease control are revealed by Duvall et al. (2019), who link host-seeking behavioral modulation in Aedes aegypti to neuropeptide Y (NPY)-like receptor 7. Small-molecule screening yields agonist compounds able to activate NPYLR7 and suppress attraction to hosts. Read More

Cell 2019 Jan 25. Epub 2019 Jan 25.

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address:

Lung cancer is closely associated with chronic inflammation, but the causes of inflammation and the specific immune mediators have not been fully elucidated. The lung is a mucosal tissue colonized by a diverse bacterial community, and pulmonary infections commonly present in lung cancer patients are linked to clinical outcomes. Here, we provide evidence that local microbiota provoke inflammation associated with lung adenocarcinoma by activating lung-resident γδ T cells. Read More

Cell 2019 Jan 28. Epub 2019 Jan 28.

Center for Brain Science and Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address:

High-acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible organisms lack a fovea, its specialized function and its dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate comprehensive cellular taxonomies of macaque fovea and peripheral retina. Read More

Cell 2019 Feb 31;176(4):928-943.e22. Epub 2019 Jan 31.

Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Systems Biology Harvard Medical School, Boston, MA 02125, USA. Electronic address:

Understanding the molecular programs that guide differentiation during development is a major challenge. Here, we introduce Waddington-OT, an approach for studying developmental time courses to infer ancestor-descendant fates and model the regulatory programs that underlie them. We apply the method to reconstruct the landscape of reprogramming from 315,000 single-cell RNA sequencing (scRNA-seq) profiles, collected at half-day intervals across 18 days. Read More

Cell 2019 Jan 25. Epub 2019 Jan 25.

Cutaneous Leukocyte Biology Section, Dermatology Branch, NIAMS, NIH, Bethesda, MD 20892, USA. Electronic address:

Immune cells and epithelium form sophisticated barrier systems in symbiotic relationships with microbiota. Evidence suggests that immune cells can sense microbes through intact barriers, but regulation of microbial commensalism remain largely unexplored. Here, we uncovered spatial compartmentalization of skin-resident innate lymphoid cells (ILCs) and modulation of sebaceous glands by a subset of RORγt ILCs residing within hair follicles in close proximity to sebaceous glands. Read More

Cell 2019 Jan 25. Epub 2019 Jan 25.

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Sphingomyelin and cholesterol are essential lipids that are enriched in plasma membranes of animal cells, where they interact to regulate membrane properties and many intracellular signaling processes. Despite intense study, the interaction between these lipids in membranes is not well understood. Here, structural and biochemical analyses of ostreolysin A (OlyA), a protein that binds to membranes only when they contain both sphingomyelin and cholesterol, reveal that sphingomyelin adopts two distinct conformations in membranes when cholesterol is present. Read More

Cell 2019 Feb 31;176(4):716-728.e18. Epub 2019 Jan 31.

Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul 03080, Republic of Korea; Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address:

Sensory axons degenerate following separation from their cell body, but partial injury to peripheral nerves may leave the integrity of damaged axons preserved. We show that an endogenous ligand for the natural killer (NK) cell receptor NKG2D, Retinoic Acid Early 1 (RAE1), is re-expressed in adult dorsal root ganglion neurons following peripheral nerve injury, triggering selective degeneration of injured axons. Infiltration of cytotoxic NK cells into the sciatic nerve by extravasation occurs within 3 days following crush injury. Read More

Cell 2019 Feb 31;176(4):844-855.e15. Epub 2019 Jan 31.

Joseph Henry Laboratories of Physics and the Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Developmental and Stem Cell Biology, UMR3738, Institut Pasteur, 75015 Paris, France. Electronic address:

In developing organisms, spatially prescribed cell identities are thought to be determined by the expression levels of multiple genes. Quantitative tests of this idea, however, require a theoretical framework capable of exposing the rules and precision of cell specification over developmental time. We use the gap gene network in the early fly embryo as an example to show how expression levels of the four gap genes can be jointly decoded into an optimal specification of position with 1% accuracy. Read More

Cell 2019 Jan 25. Epub 2019 Jan 25.

Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre (UMC) Utrecht, 3584 CT Utrecht, the Netherlands; Oncode Institute, Hubrecht Institute, 3584 CT Utrecht, the Netherlands; Princess Máxima Centre for Paediatric Oncology, 3584 CT Utrecht, the Netherlands. Electronic address:

Homeostatic regulation of the intestinal enteroendocrine lineage hierarchy is a poorly understood process. We resolved transcriptional changes during enteroendocrine differentiation in real time at single-cell level using a novel knockin allele of Neurog3, the master regulator gene briefly expressed at the onset of enteroendocrine specification. A bi-fluorescent reporter, Neurog3Chrono, measures time from the onset of enteroendocrine differentiation and enables precise positioning of single-cell transcriptomes along an absolute time axis. Read More

Cell 2019 Jan 31. Epub 2019 Jan 31.

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Department of Neurobiology, Stanford University, Stanford, CA 94305, USA. Electronic address:

Sexually naive animals have to distinguish between the sexes because they show species-typical interactions with males and females without meaningful prior experience. However, central neural pathways in naive mammals that recognize sex of other individuals remain poorly characterized. We examined the role of the principal component of the bed nucleus of stria terminalis (BNSTpr), a limbic center, in social interactions in mice. Read More

Cell 2019 Jan 24. Epub 2019 Jan 24.

Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address:

Activating mutations in NRAS account for 20%-30% of melanoma, but despite decades of research and in contrast to BRAF, no effective anti-NRAS therapies have been forthcoming. Here, we identify a previously uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation. Read More

Cell 2019 Feb 31;176(4):757-774.e23. Epub 2019 Jan 31.

Barts Cancer Institute, John Vane Science Building, Charterhouse Square, Queen Mary University of London, London EC1M 6BQ, UK; Randall Centre for Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London SE1 1UL, UK. Electronic address:

ROCK-Myosin II drives fast rounded-amoeboid migration in cancer cells during metastatic dissemination. Analysis of human melanoma biopsies revealed that amoeboid melanoma cells with high Myosin II activity are predominant in the invasive fronts of primary tumors in proximity to CD206CD163 tumor-associated macrophages and vessels. Proteomic analysis shows that ROCK-Myosin II activity in amoeboid cancer cells controls an immunomodulatory secretome, enabling the recruitment of monocytes and their differentiation into tumor-promoting macrophages. Read More

Cell 2019 Jan 23. Epub 2019 Jan 23.

Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA. Electronic address:

Recent outbreaks of severe acute respiratory syndrome and Middle East respiratory syndrome, along with the threat of a future coronavirus-mediated pandemic, underscore the importance of finding ways to combat these viruses. The trimeric spike transmembrane glycoprotein S mediates entry into host cells and is the major target of neutralizing antibodies. To understand the humoral immune response elicited upon natural infections with coronaviruses, we structurally characterized the SARS-CoV and MERS-CoV S glycoproteins in complex with neutralizing antibodies isolated from human survivors. Read More

Cell 2019 Jan 17. Epub 2019 Jan 17.

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

Collateral arteries are an uncommon vessel subtype that can provide alternate blood flow to preserve tissue following vascular occlusion. Some patients with heart disease develop collateral coronary arteries, and this correlates with increased survival. However, it is not known how these collaterals develop or how to stimulate them. Read More

Cell 2019 Feb 24;176(4):913-927.e18. Epub 2019 Jan 24.

Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada. Electronic address:

Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to cardiac chamber specification and platform versatility can be overcome. We describe here a scalable tissue-cultivation platform that is cell source agnostic and enables drug testing under electrical pacing. The plastic platform enabled on-line noninvasive recording of passive tension, active force, contractile dynamics, and Ca transients, as well as endpoint assessments of action potentials and conduction velocity. Read More

Cell 2019 Jan 21. Epub 2019 Jan 21.

Department of Biological Sciences, Howard Hughes Medical Institute, Columbia University, New York, NY 10027, USA. Electronic address:

The specific patterns and functional properties of electrical synapses of a nervous system are defined by the neuron-specific complement of electrical synapse constituents. We systematically examined the molecular composition of the electrical connectome of the nematode C. elegans through a genome- and nervous-system-wide analysis of the expression patterns of the invertebrate electrical synapse constituents, the innexins. Read More

Cell 2019 Feb 24;176(4):897-912.e20. Epub 2019 Jan 24.

Department of Immunology, Harvard Medical School, Boston, MA, USA. Electronic address:

A complete chart of cis-regulatory elements and their dynamic activity is necessary to understand the transcriptional basis of differentiation and function of an organ system. We generated matched epigenome and transcriptome measurements in 86 primary cell types that span the mouse immune system and its differentiation cascades. This breadth of data enable variance components analysis that suggests that genes fall into two distinct classes, controlled by either enhancer- or promoter-driven logic, and multiple regression that connects genes to the enhancers that regulate them. Read More

Cell 2019 Jan;176(3):678

Cell 2019 Jan;176(3):677

Cell 2019 Jan;176(3):676

Cell 2019 Jan;176(3):636-648.e13

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300353, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; Laboratory of Structural Biology, Tsinghua University, Beijing, 100084, China. Electronic address:

Despite intensive efforts to discover highly effective treatments to eradicate tuberculosis (TB), it remains as a major threat to global human health. For this reason, new TB drugs directed toward new targets are highly coveted. MmpLs (Mycobacterial membrane proteins Large), which play crucial roles in transporting lipids, polymers and immunomodulators and which also extrude therapeutic drugs, are among the most important therapeutic drug targets to emerge in recent times. Read More

Cell 2019 Jan;176(3):625-635.e14

CAS Key Laboratory of Infection and Immunity, CAS Centre for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Programmed -1 ribosomal frameshifting (-1PRF) is a widely used translation recoding mechanism. HIV-1 expresses Gag-Pol protein from the Gag-coding mRNA through -1PRF, and the ratio of Gag to Gag-Pol is strictly maintained for efficient viral replication. Here, we report that the interferon-stimulated gene product C19orf66 (herein named Shiftless) is a host factor that inhibits the -1PRF of HIV-1. Read More

Cell 2019 Jan;176(3):419-434

Department for Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

Evidence is now mounting that liquid-liquid phase separation (LLPS) underlies the formation of membraneless compartments in cells. This realization has motivated major efforts to delineate the function of such biomolecular condensates in normal cells and their roles in contexts ranging from development to age-related disease. There is great interest in understanding the underlying biophysical principles and the specific properties of biological condensates with the goal of bringing insights into a wide range of biological processes and systems. Read More

Cell 2019 Jan;176(3):416-418

Department of Experimental Neuroimmunology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Electronic address:

By in vivo screening in zebrafish larvae, Wheeler et al. identify environmental agents that directly modulate transcriptional programs of astrocytes. The herbicide linuron exploits the unfolded protein response pathway to induce a pro-inflammatory program in reactive astrocytes that potentiates inflammatory tissue damage in the CNS. Read More

Cell 2019 Jan;176(3):414-416

Department of Systems Biology, Department of Biochemistry and Molecular Biophysics, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA. Electronic address:

The importance of genomic sequence context in generating transcriptome diversity through RNA splicing is independently unmasked by two studies in this issue (Jaganathan et al., 2019; Baeza-Centurion et al., 2019). Read More

Cell 2019 Jan;176(3):412-413

Laboratory of Genome Architecture and Dynamics, The Rockefeller University, 1230 York Ave, Box #176, New York, NY 10065, USA. Electronic address:

A method for mapping nucleosome contacts and relative nucleosome orientations reveals new detail about the folding of the S. cerevisiae genome. Two new chromatin folding patterns emerge, with one enriched and the other depleted at transcription start and end sites. Read More

Cell 2019 Jan;176(3):409-411

Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, NY, USA. Electronic address:

Structures of the cannabinoid receptor 1 (CB1) in complex with an "ultrapotent" synthetic cannabinoid and its G protein (Krishna Kumar et al., 2019) and CB2 in complex with a new rationally designed inverse agonist (Li et al., 2019) provide unique snapshots of the molecular pharmacology of cannabinoids. Read More

Cell 2019 Feb 17;176(4):790-804.e13. Epub 2019 Jan 17.

Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address:

The pancreatic islets of Langerhans regulate glucose homeostasis. The loss of insulin-producing β cells within islets results in diabetes, and islet transplantation from cadaveric donors can cure the disease. In vitro production of whole islets, not just β cells, will benefit from a better understanding of endocrine differentiation and islet morphogenesis. Read More

Cell 2019 Feb 17;176(4):702-715.e14. Epub 2019 Jan 17.

Department of Structural Biology, Genentech, South San Francisco, CA 94080, USA. Electronic address:

Voltage-gated sodium (Nav) channels are targets of disease mutations, toxins, and therapeutic drugs. Despite recent advances, the structural basis of voltage sensing, electromechanical coupling, and toxin modulation remains ill-defined. Protoxin-II (ProTx2) from the Peruvian green velvet tarantula is an inhibitor cystine-knot peptide and selective antagonist of the human Nav1. Read More

Cell 2019 Feb 17;176(4):729-742.e18. Epub 2019 Jan 17.

University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. Electronic address:

Hypothalamic melanocortin neurons play a pivotal role in weight regulation. Here, we examined the contribution of Semaphorin 3 (SEMA3) signaling to the development of these circuits. In genetic studies, we found 40 rare variants in SEMA3A-G and their receptors (PLXNA1-4; NRP1-2) in 573 severely obese individuals; variants disrupted secretion and/or signaling through multiple molecular mechanisms. Read More

Cell 2019 Jan 17;176(3):663-675.e19. Epub 2019 Jan 17.

Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address:

In order to provide a comprehensive resource for human structural variants (SVs), we generated long-read sequence data and analyzed SVs for fifteen human genomes. We sequence resolved 99,604 insertions, deletions, and inversions including 2,238 (1.6 Mbp) that are shared among all discovery genomes with an additional 13,053 (6. Read More

Cell 2019 Jan 17;176(3):649-662.e20. Epub 2019 Jan 17.

CIBIO Department, University of Trento, Trento, Italy. Electronic address:

The body-wide human microbiome plays a role in health, but its full diversity remains uncharacterized, particularly outside of the gut and in international populations. We leveraged 9,428 metagenomes to reconstruct 154,723 microbial genomes (45% of high quality) spanning body sites, ages, countries, and lifestyles. We recapitulated 4,930 species-level genome bins (SGBs), 77% without genomes in public repositories (unknown SGBs [uSGBs]). Read More

Cell 2019 Jan 17;176(3):597-609.e18. Epub 2019 Jan 17.

Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. Electronic address:

Many evolutionary years separate humans and macaques, and although the amygdala and cingulate cortex evolved to enable emotion and cognition in both, an evident functional gap exists. Although they were traditionally attributed to differential neuroanatomy, functional differences might also arise from coding mechanisms. Here we find that human neurons better utilize information capacity (efficient coding) than macaque neurons in both regions, and that cingulate neurons are more efficient than amygdala neurons in both species. Read More

Cell 2019 Jan 17;176(3):581-596.e18. Epub 2019 Jan 17.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

Genome-wide studies have identified genetic variants linked to neurologic diseases. Environmental factors also play important roles, but no methods are available for their comprehensive investigation. We developed an approach that combines genomic data, screens in a novel zebrafish model, computational modeling, perturbation studies, and multiple sclerosis (MS) patient samples to evaluate the effects of environmental exposure on CNS inflammation. Read More

Cell 2019 Jan 17;176(3):549-563.e23. Epub 2019 Jan 17.

Systems Biology Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, 08003 Barcelona, Spain; Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluís Companys 23, 08010 Barcelona, Spain. Electronic address:

Despite a wealth of molecular knowledge, quantitative laws for accurate prediction of biological phenomena remain rare. Alternative pre-mRNA splicing is an important regulated step in gene expression frequently perturbed in human disease. To understand the combined effects of mutations during evolution, we quantified the effects of all possible combinations of exonic mutations accumulated during the emergence of an alternatively spliced human exon. Read More

Cell 2019 Jan 17;176(3):535-548.e24. Epub 2019 Jan 17.

Illumina Artificial Intelligence Laboratory, Illumina, Inc., San Diego, CA, USA. Electronic address:

The splicing of pre-mRNAs into mature transcripts is remarkable for its precision, but the mechanisms by which the cellular machinery achieves such specificity are incompletely understood. Here, we describe a deep neural network that accurately predicts splice junctions from an arbitrary pre-mRNA transcript sequence, enabling precise prediction of noncoding genetic variants that cause cryptic splicing. Synonymous and intronic mutations with predicted splice-altering consequence validate at a high rate on RNA-seq and are strongly deleterious in the human population. Read More

Cell 2019 Jan 17;176(3):520-534.e25. Epub 2019 Jan 17.

Laboratory for Cell Systems Control, RIKEN Center for Biosystems Dynamics Research, 6-2-3 Furuedai, Suita, Osaka 565-0874, Japan; PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan. Electronic address:

Elucidating the global and local rules that govern genome-wide, hierarchical chromatin architecture remains a critical challenge. Current high-throughput chromosome conformation capture (Hi-C) technologies have identified large-scale chromatin structural motifs, such as topologically associating domains and looping. However, structural rules at the smallest or nucleosome scale remain poorly understood. Read More

Cell 2019 Jan 10;176(3):459-467.e13. Epub 2019 Jan 10.

iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address:

The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases. Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution. Read More