Systems biology

  • Letter |

    Maternal age is found to be a major source of phenotypic variation in isogenic C. elegans populations living in a controlled environment, with the progeny of young mothers impaired for multiple fitness traits.

    • Marcos Francisco Perez
    • , Mirko Francesconi
    •  & Ben Lehner
  • Article |

    Profiling of 53,193 individual epithelial cells from the mouse small intestine identifies previously unknown cell subtypes and corresponding gene markers, providing insight into gut homeostasis and response to pathogens.

    • Adam L. Haber
    • , Moshe Biton
    •  & Aviv Regev
  • Letter |

    Metabolic flux analysis in mice reveals that lactate often acts as the primary carbon source for the tricarboxylic acid cycle both in normal tissues and in tumour microenvironments.

    • Sheng Hui
    • , Jonathan M. Ghergurovich
    •  & Joshua D. Rabinowitz
  • Letter |

    Introducing a single ‘sticky’ (hydrophobic) amino acid by point mutation into symmetric protein complexes frequently triggers their association into higher-order assemblies, without affecting their native fold and structure.

    • Hector Garcia-Seisdedos
    • , Charly Empereur-Mot
    •  & Emmanuel D. Levy
  • Letter |

    The authors devise an algorithm that can cluster T cell receptor (TCR) sequences sharing the same specificity, predict the HLA restriction of these TCR clusters on the basis of subjects’ genotypes and help to identify specific peptide major histocompatibility complex ligands.

    • Jacob Glanville
    • , Huang Huang
    •  & Mark M. Davis
  • Letter |

    Through drug exposure, a rare, transient transcriptional program characterized by high levels of expression of known resistance drivers can get ‘burned in’, leading to the selection of cells endowed with a transcriptional drug resistance and thus more chemoresistant cancers.

    • Sydney M. Shaffer
    • , Margaret C. Dunagin
    •  & Arjun Raj
  • Article |

    The identification of the positions and patterns of amino acids that form the selectivity determinants for the entire human G-protein and G-protein-coupled receptor signalling system.

    • Tilman Flock
    • , Alexander S. Hauser
    •  & M. Madan Babu
  • Article
    | Open Access

    This paper describes molecular subtypes of cervical cancers, including squamous cell carcinoma and adenocarcinoma clusters defined by HPV status and molecular features, and distinct molecular pathways that are activated in cervical carcinomas caused by different somatic alterations and HPV types.

    • Robert D. Burk
    • , Zigui Chen
    •  & David Mutch
  • Brief Communications Arising |

    • Zhaleh Safikhani
    • , Nehme El-Hachem
    •  & Benjamin Haibe-Kains
  • Letter |

    The first synthetic genetic oscillator or ‘repressilator’ is simplified using insights from stochastic theory, thus achieving remarkably precise and robust oscillations and informing current debates about the next generation of synthetic circuits and their potential applications in cell-based therapies.

    • Laurent Potvin-Trottier
    • , Nathan D. Lord
    •  & Johan Paulsson
  • Letter |

    Clinically relevant bacteria have been engineered to lyse synchronously at a threshold population density and release genetically encoded therapeutics; treatment of mice with these bacteria slowed the growth of tumours.

    • M. Omar Din
    • , Tal Danino
    •  & Jeff Hasty
  • Letter |

    A diverse range of molecular and genetic manipulations all alter lifespan distributions of Caenorhabditis elegans by an apparent stretching or shrinking of time.

    • Nicholas Stroustrup
    • , Winston E. Anthony
    •  & Walter Fontana
  • Article |

    In-depth analyses of protein expression studies are used to derive a new codon-influence metric that correlates with global protein levels, mRNA levels and mRNA lifetimes in vivo, indicating tight coupling between translation efficiency and mRNA stability; genes redesigned based on these analyses consistently yield high protein expression levels both in vivo and in vitro.

    • Grégory Boël
    • , Reka Letso
    •  & John F. Hunt
  • Article |

    Using experimental proteomics and modelling in E. coli, the amount of protein needed to run respiration (per ATP produced) is shown to be twice as much as that needed to run fermentation; results demonstrate that overflow metabolism (known as the Warburg effect in cancer cells) is a necessary outcome of optimal bacterial growth, governed by a global resource allocation program, and that the methodology is directly applicable to synthetic biology and cancer research.

    • Markus Basan
    • , Sheng Hui
    •  & Terence Hwa
  • Article |

    A new deep proteomic analysis method is used to identify proteins that interact with wild-type cystic fibrosis transmembrane conductance regulator (CFTR) and its mutant version that is the major cause of cystic fibrosis.

    • Sandra Pankow
    • , Casimir Bamberger
    •  & John R. Yates III
  • Article |

    Ion channels in bacterial biofilms are shown to conduct long-range electrical signals within the biofilm community through the propagation of potassium ions; as predicted by a simple mathematical model, potassium channel gating is shown to coordinate metabolic states between distant cells via electrical communication.

    • Arthur Prindle
    • , Jintao Liu
    •  & Gürol M. Süel
  • Article |

    Many gene-regulatory proteins have been shown to activate in pulses, but whether cells exploit the dynamic interaction between pulses of different regulatory proteins has remained unexplored; here single-cell videos show that yeast cells modulate the relative timing between the pulsatile transcription factors Msn2 and Mig1—a gene activator and a repressor, respectively—to control the expression of target genes in response to diverse environmental conditions.

    • Yihan Lin
    • , Chang Ho Sohn
    •  & Michael B. Elowitz
  • Letter |

    The Trivers–Willard theory proposing that maternal condition influences offspring sex ratio is extended by analysing how differences in mortality rates, age‐specific reproduction and life history tactics between males and females may affect adaptive offspring sex ratio adjustment in two systems.

    • Susanne Schindler
    • , Jean‐Michel Gaillard
    •  & Tim Coulson
  • Article |

    Using biochemical fractionation and mass spectrometry, animal protein complexes are identified from nine species in parallel, and, along with genome sequence information, complex conservation is investigated and over one million protein–protein interactions are predicted in 122 eukaryotes.

    • Cuihong Wan
    • , Blake Borgeson
    •  & Andrew Emili
  • Letter |

    An algorithm that allows rare cell type identification in a complex population of single cells, based on single-cell mRNA-sequencing, is applied to mouse intestinal cells, revealing novel subtypes of enteroendocrine cells and showing that the Lgr5-expressing population consists of a homogenous stem cell population with a few rare secretory cells, including Paneth cells.

    • Dominic Grün
    • , Anna Lyubimova
    •  & Alexander van Oudenaarden
  • Letter |

    A ribosome with tethered subunits, ‘Ribo-T’, is engineered by making a hybrid RNA composed of ribosomal RNA of large and small subunits; Ribo-T can support cell growth in vivo in the absence of wild-type ribosomes, and is used to establish a fully orthogonal ribosome–mRNA system.

    • Cédric Orelle
    • , Erik D. Carlson
    •  & Alexander S. Mankin
  • Letter |

    Epistatic interactions, whereby a mutation's effect is contingent on another mutation, have been shown to constrain evolution within single proteins, and how such interactions arise in gene regulatory networks has remained unclear; here the appearance of pheromone-response regulator binding sites in the regulatory DNA of the a-specific genes of Saccharomyces cerevisiae are shown to have required specific changes in a second pathway during the evolution from its common ancestor with Candida albicans.

    • Trevor R. Sorrells
    • , Lauren N. Booth
    •  & Alexander D. Johnson
  • Letter |

    A single-cell method for probing genome-wide chromatin accessibility has been developed; the results provide insight into the relationship between cell-to-cell variation associated with specific trans-factors and cis-elements, as well insights into the relationship between chromatin accessibility and three-dimensional genome organization.

    • Jason D. Buenrostro
    • , Beijing Wu
    •  & William J. Greenleaf
  • Letter |

    Quantification of single-cell growth over long periods of time in E. coli shows transient oscillations in cell size, with periods stretching across more than ten generations; a noisy negative feedback on cell-size control is proposed in which cells with a small initial size tend to divide later than cells with a large initial size with implications for the genetic and physiological processes required.

    • Yu Tanouchi
    • , Anand Pai
    •  & Lingchong You
  • Letter |

    Genome-wide chromosome conformation capture analysis in C. elegans reveals that the dosage compensation complex, a condensin complex, remodels the X chromosomes of hermaphrodites into a sex-specific topology distinct from autosomes while regulating gene expression chromosome-wide.

    • Emily Crane
    • , Qian Bian
    •  & Barbara J. Meyer
  • Letter |

    Little is known about how individual cells within a group of cells exposed to the same external signals can produce a specific individual response to their local microenvironment; a quantitative analysis of cell crowding reveals that single cells can autonomously sense local crowding though their ability to spread and activate focal adhesion kinase (FAK), which ultimately results in changes in cellular lipid composition.

    • Mathieu Frechin
    • , Thomas Stoeger
    •  & Lucas Pelkmans
  • Letter |

    A method, termed hiCLIP, has been developed to determine the RNA duplexes bound by RNA-binding proteins, revealing an unforeseen prevalence of long-range duplexes in 3′ untranslated regions (UTRs), and a decreased incidence of SNPs in duplex-forming regions; the results also show that RNA structure is able to regulate gene expression.

    • Yoichiro Sugimoto
    • , Alessandra Vigilante
    •  & Jernej Ule
  • Letter |

    Precise measurement of cell-cycle duration in thousands of mammalian cells reveals correlations among cousin cells, but no such correlations between mother and daughter cells; recapitulating this finding using a deterministic model suggests that observed cellular heterogeneities in cell-cycle duration may be attributable to deterministic processes, and eventually be controlled.

    • Oded Sandler
    • , Sivan Pearl Mizrahi
    •  & Nathalie Q. Balaban
  • Article
    | Open Access

    This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.

    • Anshul Kundaje
    • , Wouter Meuleman
    •  & Manolis Kellis
  • Article |

    The full complement of transcriptional regulators that affect synthesis of the plant secondary cell wall remains largely undetermined; here, the network of protein–DNA interactions controlling secondary cell wall synthesis of Arabidopsis thaliana is determined, showing that gene expression is regulated by a series of feed-forward loops to ensure that the secondary cell wall is deposited at the right time and in the right place.

    • M. Taylor-Teeples
    • , L. Lin
    •  & S. M. Brady
  • Letter |

    A protein degradation pathway is found at the inner nuclear membrane that is distinct from, but complementary to, endoplasmic-reticulum-associated protein degradation, and which is mediated by the Asi protein complex; a genome-wide library screening of yeast identifies more than 20 substrates of this pathway, which is shown to target mislocalized integral membrane proteins for degradation.

    • Anton Khmelinskii
    • , Ewa Blaszczak
    •  & Michael Knop
  • Article |

    This study uses single-cell expression profiling of pluripotent stem cells after various perturbations, and uncovers a high degree of variability that can be inherited through cell divisions—modulating microRNA or external signalling pathways induces a ground state with reduced gene expression heterogeneity and a distinct chromatin profile.

    • Roshan M. Kumar
    • , Patrick Cahan
    •  & James J. Collins
  • Letter |

    Protease competition is used to produce rapid and tunable coupling of genetic circuits, enabling a coupled clock network that can encode independent environmental cues into a single time series output, a form of frequency multiplexing in a genetic circuit context.

    • Arthur Prindle
    • , Jangir Selimkhanov
    •  & Jeff Hasty
  • Article |

    A study from the FANTOM consortium using single-molecule cDNA sequencing of transcription start sites and their usage in human and mouse primary cells, cell lines and tissues reveals insights into the specificity and diversity of transcription patterns across different mammalian cell types.

    • Alistair R. R. Forrest
    • , Hideya Kawaji
    •  & Yoshihide Hayashizaki
  • Article |

    This study shows that Bacillus subtilis switches from a solitary, motile lifestyle to a multicellular, sessile state in a random, memoryless fashion, but that the underlying gene network is buffered against its own stochastic variation to tightly time the reverse transition; thus bacteria keep track of time to force their progeny to cooperate during the earliest stage of multicellular growth.

    • Thomas M. Norman
    • , Nathan D. Lord
    •  & Richard Losick
  • Article |

    Cyclic AMP, one of the earliest discovered and most intensely studied signalling molecules in molecular biology, is widely believed to signal the carbon status in mediating catabolite repression in bacteria; here a quantitative approach reveals a much broader physiological role for cAMP signalling, whereby it coordinates the allocation of proteomic resources with the global metabolic needs of the cell, including, for example, nitrogen or sulphur.

    • Conghui You
    • , Hiroyuki Okano
    •  & Terence Hwa