Functional genomics articles within Nature

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  • Article |

    The authors describe a two-cell-type CRISPR screen to identify tumour-intrinsic genes that regulate the sensitivity of cancer cells to effector T cell function.

    • Shashank J. Patel
    • , Neville E. Sanjana
    •  & Nicholas P. Restifo

  • Article |

    In vivo CRISPR screening reveals that loss of Ptpn2 increases the response of tumour cells to immunotherapy and increases IFNγ signalling, suggesting that PTPN2 inhibition may potentiate the effect of immunotherapies that invoke an IFNγ response.

    • Robert T. Manguso
    • , Hans W. Pope
    •  & W. Nicholas Haining

  • Article |

    Identification and characterization, using a comprehensive embryonic phenotyping pipeline, of 410 lethal alleles during the generation of the first 1,751 of 5,000 unique gene knockouts produced by the International Mouse Phenotyping Consortium.

    • Mary E. Dickinson
    • , Ann M. Flenniken
    •  & Stephen A. Murray

  • Letter |

    A CRISPR screening approach shows that endoplasmic reticulum (ER)-associated protein complexes, including the oligosaccharyltransferase (OST) protein complex, are important for infection by dengue virus and other related mosquito-borne flaviviruses, whereas hepatitis C virus is dependent on distinct entry factors, RNA binding proteins and FAD biosynthesis.

    • Caleb D. Marceau
    • , Andreas S. Puschnik
    •  & Jan E. Carette

  • Article |

    PRDM9 is a DNA-binding protein that controls the position of double-strand breaks in meiosis, and the gene that encodes it is responsible for hybrid infertility between closely related mouse species; this hybrid infertility is eliminated by introducing the zinc-finger domain sequence from the human version of the PRDM9 gene, a change which alters both the position of double-strand breaks and the symmetry of PRDM9 binding and suggests that PRDM9 may have a more general but transient role in the early stages of speciation.

    • Benjamin Davies
    • , Edouard Hatton
    •  & Peter Donnelly

  • Letter |

    Splicing factors such as BUD31 are identified in a synthetic-lethal screen with cells overexpressing the transcription factor MYC; oncogenic MYC leads to an increase in pre-mRNA synthesis, and spliceosome inhibition impairs the growth and tumorigenicity of MYC-dependent breast cancers, suggesting that spliceosome components may be potential therapeutic targets for MYC-driven cancers.

    • Tiffany Y.-T. Hsu
    • , Lukas M. Simon
    •  & Thomas F. Westbrook

  • Letter |

    This study demonstrates a role for the Integrator complex in the stimulus-dependent induction of eRNAs and their 3′ processing; together with previously known roles of Integrator in transcription elongation and RNA processing, these results indicate that Integrator has broad functions in the regulation of eukaryotic gene expression.

    • Fan Lai
    • , Alessandro Gardini
    •  & Ramin Shiekhattar

  • Letter |

    Patterns of amino acid conservation have been used to guide the interpretation of the disease-causing potential of genetic variants in patients; now, an appreciable fraction of pathogenic alleles are shown to be fixed in the genomes of other species, suggesting that the genomic context has an important role in allele pathogenicity.

    • Daniel M. Jordan
    • , Stephan G. Frangakis
    •  & Nicholas Katsanis

  • Article
    | Open Access

    As part of the mouse ENCODE project, genome-wide transcription factor (TF) occupancy repertoires and co-association patterns in mice and humans are studied; many aspects are conserved but the extent to which orthologous DNA segments are bound by TFs in mice and humans varies both among TFs and genomic location, and TF-occupied sequences whose occupancy is conserved tend to be pleiotropic and enriched for single nucleotide variants with known regulatory potential.

    • Yong Cheng
    • , Zhihai Ma
    •  & Michael P. Snyder

  • Article |

    DNA double-stranded breaks (DSBs) are shown to form in greater numbers in yeast cells lacking ZMM proteins, which are traditionally regarded as acting strictly downstream of DSB formation; these findings shed light on how cells balance the beneficial and deleterious outcomes of DSB formation.

    • Drew Thacker
    • , Neeman Mohibullah
    •  & Scott Keeney

  • Article
    | Open Access

    A large-scale transcriptome analysis in Drosophila melanogaster, across tissues, cell types and conditions, provides insights into global patterns and diversity of transcription initiation, splicing, polyadenylation and non-coding RNA expression.

    • James B. Brown
    • , Nathan Boley
    •  & Susan E. Celniker

  • Article |

    Evolutionary study of long noncoding RNA (lncRNA) repertoires and expression patterns in 11 tetrapod species identifies approximately 11,000 primate-specific lncRNAs and 2,500 highly conserved lncRNAs, including approximately 400 genes that are likely to have ancient origins; many lncRNAs, particularly ancient ones, are actively regulated and may function mainly in embryonic development.

    • Anamaria Necsulea
    • , Magali Soumillon
    •  & Henrik Kaessmann

  • Letter |

    A risk haplotype for type 2 diabetes is identified with four amino acid substitutions in SLC16A11, which is present at ∼50% frequency in Native American samples and ∼10% in east Asian samples, but is rare in European and African samples; SLC16A11 may alter hepatic lipid metabolism, causing an increase in triacylglycerol levels.

    • Amy L. Williams
    • , Suzanne B. R. Jacobs
    •  & Teresa Tusié-Luna

  • Analysis |

    This Analysis compares two large-scale pharmacogenomic data sets that catalogued the sensitivity of a large number of cancer cell lines to approved and potential drugs, and finds that whereas the gene expression data are largely concordant between the two studies, the reported drug sensitivity measures and subsequently their association with genomic features are highly discordant.

    • Benjamin Haibe-Kains
    • , Nehme El-Hachem
    •  & John Quackenbush

  • Article |

    Sequencing and deep analysis of mRNA and miRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project reveal widespread genetic variation affecting the regulation of most genes, with transcript structure and expression level variation being equally common but genetically largely independent, and the analyses point to putative causal variants for dozens of disease-associated loci.

    • Tuuli Lappalainen
    • , Michael Sammeth
    •  & Emmanouil T. Dermitzakis

  • Article |

    Here, the first genome-wide in vivo RNA interference screens in a mammalian animal model are reported: genes involved in normal and abnormal epithelial cell growth are studied in developing skin tissue in mouse embryos, and among the findings, β-catenin is shown to act as an antagonist to normal epithelial cell growth as well as promoting oncogene-driven growth.

    • Slobodan Beronja
    • , Peter Janki
    •  & Elaine Fuchs

  • News & Views |

    A quantitative analysis shows that epistasis — the fact that genetic background determines whether a mutation is beneficial, deleterious or inconsequential — is the main factor regulating evolution at the level of proteins. See Letter p.535

    • Günter P. Wagner

  • Article
    | Open Access

    An integrated high-resolution genetic, physical and shotgun sequence assembly of the barley genome, one of the earliest domesticated and most important crops, is described; it will provide a platform for genome-assisted research and future crop improvement.

    • Klaus F. X. Mayer
    • , Robbie Waugh
    •  & Nils Stein

  • Letter |

    A comparison of more than 1,000 orthologues of diverse proteins shows that the rate of amino-acid substitution in recent evolution is an order of magnitude lower than that expected in the absence of epistasis, indicating that epistasis is pervasive throughout protein evolution.

    • Michael S. Breen
    • , Carsten Kemena
    •  & Fyodor A. Kondrashov

  • Letter |

    Although zebrafish is an important animal model for basic vertebrate biology and human disease modelling, rapid targeted genome modification has not been possible in this species; here a technique based on improved artificial transcription activator-like effector nucleases (TALENs) allows precise sequence modifications at pre-determined genomic locations.

    • Victoria M. Bedell
    • , Ying Wang
    •  & Stephen C. Ekker

  • Letter |

    Genetic analysis of breakthrough infections in people vaccinated against HIV-1 show that vaccine efficacy increased by up to 80% against viruses carrying two mutations in Env V2, but also raises the possibility of population-level adaptation to the vaccine.

    • Morgane Rolland
    • , Paul T. Edlefsen
    •  & Jerome H. Kim

  • Editorial |

    Publication of ENCODE data drives innovation in data mining.

  • Introduction |

    • Magdalena Skipper
    • , Ritu Dhand
    •  & Philip Campbell

  • Comment |

    To be successful, consortia need clear management, codes of conduct and participants who are committed to working for the common good, says ENCODE lead analysis coordinator Ewan Birney.

    • Ewan Birney

  • News & Views Forum |

    The Encyclopedia of DNA Elements (ENCODE) project dishes up a hearty banquet of data that illuminate the roles of the functional elements of the human genome. Here, six scientists describe the project and discuss how the data are influencing research directions across many fields. See Articles p.57, p.75, p.83, p.91, p.101 & Letter p.109

    • Joseph R. Ecker
    • , Wendy A. Bickmore
    •  & Eran Segal

  • News Feature |

    First they sequenced it. Now they have surveyed its hinterlands. But no one knows how much more information the human genome holds, or when to stop looking for it.

    • Brendan Maher

  • Article
    | Open Access

    This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

    • Ian Dunham
    • , Anshul Kundaje
    •  & Ewan Birney

  • Letter
    | Open Access

    Chromosome conformation capture carbon copy (5C) is used to look at the relationships between functional elements and distal target genes in 1% of the human genome in three dimensions; the study describes numerous long-range interactions between promoters and distal sites that include elements resembling enhancers, promoters and CTCF-bound sites, their genomic distribution and complex interactions.

    • Amartya Sanyal
    • , Bryan R. Lajoie
    •  & Job Dekker

  • Technology Feature |

    As more mutations are found across the genome, geneticists are focusing on learning which ones are likely to cause human disease, and how.

    • Monya Baker

  • Article |

    A meta-analysis of genome-wide association studies in more than 66,000 individuals identifies 68 new genomic loci that reliably associate with platelet count and volume, and reveals new gene functions.

    • Christian Gieger
    • , Aparna Radhakrishnan
    •  & Nicole Soranzo

  • Letter |

    Realizing the full potential of human embryonic stem cells (hESCs) in research and clinical applications requires a detailed understanding of the genetic network that governs their unique properties. A genome-wide RNA interference screen identifies a wealth of new regulators of self-renewal and pluripotency properties in hESCs. The transcription factor PRDM14, for example, is required for the maintenance of hESC identity and reprogramming of somatic cells to pluripotency.

    • Na-Yu Chia
    • , Yun-Shen Chan
    •  & Huck-Hui Ng

  • Letter |

    The blood–brain barrier (BBB) is made up of vascular endothelial cells and was thought to have formed postnatally from astrocytes. Two independent studies demonstrate that this barrier forms during embryogenesis, with pericyte/endothelial cell interactions being critical to regulate the BBB during development. A better understanding of the relationship among pericytes, neuroendothelial cells and astrocytes in BBB function will contribute to our understanding of BBB breakdown during central nervous system injury and disease.

    • Annika Armulik
    • , Guillem Genové
    •  & Christer Betsholtz

  • Article |

    The uptake of calcium by mitochondria has a central role in cell physiology, and an imbalance can trigger cell death. Now the first protein that is localized to the mitochondrion and is specifically required for calcium uptake has been identified. This protein, mitochondrial calcium uptake 1 (MICU1), represents the founding member of a set of proteins required for high-capacity calcium uptake. Its discovery should aid in the full molecular characterization of the mitochondrial calcium uptake pathways.

    • Fabiana Perocchi
    • , Vishal M. Gohil
    •  & Vamsi K. Mootha

  • News |

    How human proteins are made from DNA can be followed in real time.

    • Brendan Borrell

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