Systems biology

  • Article
    | Open Access

    Local activity of the DNA methylation machinery remains poorly understood. Here, the authors present a theoretical and experimental framework to infer methylation and demethylation rates at genome scale in mouse embryonic stem cells, finding that maintenance methylation activity is reduced at transcription factor binding sites, while methylation turnover is elevated in transcribed gene bodies.

    • Paul Adrian Ginno
    • , Dimos Gaidatzis
    • , Angelika Feldmann
    • , Leslie Hoerner
    • , Dilek Imanci
    • , Lukas Burger
    • , Frederic Zilbermann
    • , Antoine H. F. M. Peters
    • , Frank Edenhofer
    • , Sébastien A. Smallwood
    • , Arnaud R. Krebs
    •  & Dirk Schübeler
  • Article
    | Open Access

    mRNA translation efficiency is regulated in response to stimuli. Here the authors employ mass spectrometry analysis of ribosome fractions and show that under hypoxia, oxygen-sensitive RNA binding proteins enhance the translation efficiency of glycolysis pathway transcripts.

    • J. J. David Ho
    • , Nathan C. Balukoff
    • , Phaedra R. Theodoridis
    • , Miling Wang
    • , Jonathan R. Krieger
    • , Jonathan H. Schatz
    •  & Stephen Lee
  • Article
    | Open Access

    Over 100 million of opioid prescriptions are issued yearly in the USA alone, but the impact of opioid use on the immune system is barely characterized. Here the authors report antiviral immune response is blunted in several types of blood cells from opioid-dependent individuals, and when healthy donor cells are exposed to morphine in a dish.

    • Tanya T. Karagiannis
    • , John P. Cleary Jr
    • , Busra Gok
    • , Andrew J. Henderson
    • , Nicholas G. Martin
    • , Masanao Yajima
    • , Elliot C. Nelson
    •  & Christine S. Cheng
  • Article
    | Open Access

    The association between leguminous plants and rhizobial bacteria is a paradigmatic example of a symbiosis driven by metabolic exchanges. Here, diCenzo et al. report the reconstruction and modelling of a genome-scale metabolic network of the plant Medicago truncatula nodulated by the bacterium Sinorhizobium meliloti.

    • George C. diCenzo
    • , Michelangelo Tesi
    • , Thomas Pfau
    • , Alessio Mengoni
    •  & Marco Fondi
  • Article
    | Open Access

    The cytokine IFNα is expressed in the islets of individuals with type 1 diabetes and contributes to local inflammation and destruction of beta cells. Here, the authors provide a global multiomics view of IFNα-induced changes in human beta cells at the level of chromatin, mRNA and protein expression.

    • Maikel L. Colli
    • , Mireia Ramos-Rodríguez
    • , Ernesto S. Nakayasu
    • , Maria I. Alvelos
    • , Miguel Lopes
    • , Jessica L. E. Hill
    • , Jean-Valery Turatsinze
    • , Alexandra Coomans de Brachène
    • , Mark A. Russell
    • , Helena Raurell-Vila
    • , Angela Castela
    • , Jonàs Juan-Mateu
    • , Bobbie-Jo M. Webb-Robertson
    • , Lars Krogvold
    • , Knut Dahl-Jorgensen
    • , Lorella Marselli
    • , Piero Marchetti
    • , Sarah J. Richardson
    • , Noel G. Morgan
    • , Thomas O. Metz
    • , Lorenzo Pasquali
    •  & Décio L. Eizirik
  • Article
    | Open Access

    Current machine learning classifiers have been applied to whole-genome sequencing data to identify determinants of antimicrobial resistance, but they lack interpretability. Here the authors present a metabolic machine learning classifier that uses flux balance analysis to estimate the biochemical effects of alleles.

    • Erol S. Kavvas
    • , Laurence Yang
    • , Jonathan M. Monk
    • , David Heckmann
    •  & Bernhard O. Palsson
  • Article
    | Open Access

    Identification of low abundance proteins interacting with viral proteins can be challenging. Here, Du et al. develop an mRNA display approach with a library of even distribution, identify host proteins interacting with NS1 protein of influenza A virus, and show that one interactor provides a means to regulate cellular fatty acids synthesis.

    • Yushen Du
    • , Judd F. Hultquist
    • , Quan Zhou
    • , Anders Olson
    • , Yenwen Tseng
    • , Tian-hao Zhang
    • , Mengying Hong
    • , Kejun Tang
    • , Liubo Chen
    • , Xiangzhi Meng
    • , Michael J. McGregor
    • , Lei Dai
    • , Danyang Gong
    • , Laura Martin-Sancho
    • , Sumit Chanda
    • , Xinming Li
    • , Steve Bensenger
    • , Nevan J. Krogan
    •  & Ren Sun
  • Article
    | Open Access

    Fermentation parameters of industrial processes are often not the ideal growth conditions for industrial microbes. Here, the authors reveal that young genes are more responsive to environmental stress than ancient genes using a new gene age assignment method and provide targeted genes for metabolic engineering.

    • Tyler W. Doughty
    • , Iván Domenzain
    • , Aaron Millan-Oropeza
    • , Noemi Montini
    • , Philip A. de Groot
    • , Rui Pereira
    • , Jens Nielsen
    • , Céline Henry
    • , Jean-Marc G. Daran
    • , Verena Siewers
    •  & John P. Morrissey
  • Article
    | Open Access

    The origin of the heterogeneity of metabolic and inflammatory profiles exhibited by white adipocytes is little understood. Here, using scRNA-seq and computational methods, the authors show that differentiating preadipocytes exhibit gene expression differences and suggest underlying regulators.

    • Alfred K. Ramirez
    • , Simon N. Dankel
    • , Bashir Rastegarpanah
    • , Weikang Cai
    • , Ruidan Xue
    • , Mark Crovella
    • , Yu-Hua Tseng
    • , C. Ronald Kahn
    •  & Simon Kasif
  • Article
    | Open Access

    Synthetic genetic circuits are sensitive to their environment and host cell, requiring many rounds of physical reassembly to achieve a desired function. Here the authors use a multi-level regulatory motif to dynamically tune the function of genetic parts as a step towards robust adaptive circuits.

    • Vittorio Bartoli
    • , Grace A. Meaker
    • , Mario di Bernardo
    •  & Thomas E. Gorochowski
  • Article
    | Open Access

    Beta-lactam antibiotics and beta-lactamase inhibitors compete for the same binding site on beta-lactamases; thus, mutations that increase beta-lactamase activity likely increase also susceptibility to the inhibitor. Here, Russ et al. identify rare mutations in the ampC beta-lactamase gene that escape this adaptive tradeoff specifically for certain drug combinations.

    • Dor Russ
    • , Fabian Glaser
    • , Einat Shaer Tamar
    • , Idan Yelin
    • , Michael Baym
    • , Eric D. Kelsic
    • , Claudia Zampaloni
    • , Andreas Haldimann
    •  & Roy Kishony
  • Article
    | Open Access

    Epithelial gene expression has been shown to be zonated along the crypt-villus axis, but mechanisms shaping this spatial variability were unknown. Here, Bahar Halpern et al. uncover zonation of mesenchymal cells, including Lgr5+ telocytes, which regulate epithelial gene expression at the villus tip.

    • Keren Bahar Halpern
    • , Hassan Massalha
    • , Rachel K. Zwick
    • , Andreas E. Moor
    • , David Castillo-Azofeifa
    • , Milena Rozenberg
    • , Lydia Farack
    • , Adi Egozi
    • , Dan R. Miller
    • , Inna Averbukh
    • , Yotam Harnik
    • , Noa Weinberg-Corem
    • , Frederic J. de Sauvage
    • , Ido Amit
    • , Ophir D. Klein
    • , Michal Shoshkes-Carmel
    •  & Shalev Itzkovitz
  • Article
    | Open Access

    Evolutionary steering uses therapies to control tumour evolution by exploiting trade-offs. Here, using a barcoding approach applied to large cell populations, the authors explore evolutionary steering in lung cancer cells treated with EGFR inhibitors.

    • Ahmet Acar
    • , Daniel Nichol
    • , Javier Fernandez-Mateos
    • , George D. Cresswell
    • , Iros Barozzi
    • , Sung Pil Hong
    • , Nicholas Trahearn
    • , Inmaculada Spiteri
    • , Mark Stubbs
    • , Rosemary Burke
    • , Adam Stewart
    • , Giulio Caravagna
    • , Benjamin Werner
    • , Georgios Vlachogiannis
    • , Carlo C. Maley
    • , Luca Magnani
    • , Nicola Valeri
    • , Udai Banerji
    •  & Andrea Sottoriva
  • Article
    | Open Access

    Cells maintain reserves in their metabolic and translational capacities enabling fast response to changing environments. Here, the authors quantify reserves in yeast by stepwise reduction in nitrogen availability and a combination of multi-omic analysis and metabolic modelling.

    • Rosemary Yu
    • , Kate Campbell
    • , Rui Pereira
    • , Johan Björkeroth
    • , Qi Qi
    • , Egor Vorontsov
    • , Carina Sihlbom
    •  & Jens Nielsen
  • Article
    | Open Access

    Cytokines critically control the differentiation and functions of activated naïve and memory T cells. Here the authors show, using multi-omics and single-cell analyses, that naïve and memory T cells exhibit distinct cytokine responses, in which an ‘effectorness gradient’ is depicted by a transcriptional continuum, which shapes the downstream genetic programs.

    • Eddie Cano-Gamez
    • , Blagoje Soskic
    • , Theodoros I. Roumeliotis
    • , Ernest So
    • , Deborah J. Smyth
    • , Marta Baldrighi
    • , David Willé
    • , Nikolina Nakic
    • , Jorge Esparza-Gordillo
    • , Christopher G. C. Larminie
    • , Paola G. Bronson
    • , David F. Tough
    • , Wendy C. Rowan
    • , Jyoti S. Choudhary
    •  & Gosia Trynka
  • Article
    | Open Access

    Current synthetic DNA-based data storage systems have high recording costs, read-write latency and error-rates that make them uncompetitive compared to traditional digital storage. The authors use nicks in native DNA to encode data in parallel and create access sites for in-memory computations.

    • S. Kasra Tabatabaei
    • , Boya Wang
    • , Nagendra Bala Murali Athreya
    • , Behnam Enghiad
    • , Alvaro Gonzalo Hernandez
    • , Christopher J. Fields
    • , Jean-Pierre Leburton
    • , David Soloveichik
    • , Huimin Zhao
    •  & Olgica Milenkovic
  • Review Article
    | Open Access

    Multiplexed CRISPR technologies have recently emerged as powerful approaches for genetic editing and transcriptional regulation. Here the authors review this emerging technology and discuss challenges and considerations for future studies.

    • Nicholas S. McCarty
    • , Alicia E. Graham
    • , Lucie Studená
    •  & Rodrigo Ledesma-Amaro
  • Article
    | Open Access

    Genome-scale models of microbial metabolism largely ignore reaction kinetics. Here, the authors develop a general mathematical framework for modeling cellular growth with explicit non-linear reaction kinetics and use it to glean insights into the principles of cellular resource allocation and growth.

    • Hugo Dourado
    •  & Martin J. Lercher
  • Article
    | Open Access

    Conventional methods cannot reveal transient transcription factors (TFs) and targets interactions. Here, Alvarez et al. capture both stable and transient TF-target interactions by time-series ChIP-seq and/or DamID-seq in a cell-based TF perturbation system and show NLP7 as a master TF to initiate a rapid nitrogen-response cascade.

    • José M. Alvarez
    • , Anna-Lena Schinke
    • , Matthew D. Brooks
    • , Angelo Pasquino
    • , Lauriebeth Leonelli
    • , Kranthi Varala
    • , Alaeddine Safi
    • , Gabriel Krouk
    • , Anne Krapp
    •  & Gloria M. Coruzzi
  • Article
    | Open Access

    Macrophage activation is tightly regulated to maintain immune homeostasis, yet activation is also heterogeneous. Here, the authors show that macrophages coordinate activation by partitioning into two phenotypes that can nonlinearly amplify collective inflammatory cytokine production as a function of cell density.

    • Joseph J. Muldoon
    • , Yishan Chuang
    • , Neda Bagheri
    •  & Joshua N. Leonard
  • Article
    | Open Access

    SCRaMbLE can lead to great genetic diversity for product biosynthesis but is limited by screening methods. Here the authors develop a rapid workflow using automation, ultra-fast LC/MS and barcoded nanopore sequencing to identify best performing strains.

    • G.-O. F. Gowers
    • , S. M. Chee
    • , D. Bell
    • , L. Suckling
    • , M. Kern
    • , D. Tew
    • , D. W. McClymont
    •  & T. Ellis
  • Article
    | Open Access

    Saccharomyces cerevisiae is a model organism to study proteins involved in neurodegeneration. Here, the authors performed a yeast genome-wide synthetic genetic interaction array (SGA) to screen for toxicity modifiers of Aβ42 and identify riboflavin kinase and its metabolic product flavin mononucleotide as modulators that alleviate cellular Aβ42 toxicity, which is supported by further experimental analyses.

    • Xin Chen
    • , Boyang Ji
    • , Xinxin Hao
    • , Xiaowei Li
    • , Frederik Eisele
    • , Thomas Nyström
    •  & Dina Petranovic
  • Article
    | Open Access

    The study of disease modules facilitates insight into complex diseases, but their identification relies on knowledge of molecular networks. Here, the authors show that disease modules and genes can also be discovered in deep autoencoder representations of large human gene expression datasets.

    • Sanjiv K. Dwivedi
    • , Andreas Tjärnberg
    • , Jesper Tegnér
    •  & Mika Gustafsson
  • Article
    | Open Access

    Genome engineering will one day benefit from computational tools that can design genomes with desired functions. Here the authors develop computational design-simulate-test algorithms to design minimal genomes based on the whole-cell model of Mycoplasma genitalium.

    • Joshua Rees-Garbutt
    • , Oliver Chalkley
    • , Sophie Landon
    • , Oliver Purcell
    • , Lucia Marucci
    •  & Claire Grierson
  • Article
    | Open Access

    Complex diseases often share genetic determinants and symptoms, but the mechanistic basis of disease interactions remains elusive. Here, the authors propose a network topological measure to identify proteins linking complex diseases in the interactome, and identify mediators between COPD and asthma.

    • Enrico Maiorino
    • , Seung Han Baek
    • , Feng Guo
    • , Xiaobo Zhou
    • , Parul H. Kothari
    • , Edwin K. Silverman
    • , Albert-László Barabási
    • , Scott T. Weiss
    • , Benjamin A. Raby
    •  & Amitabh Sharma
  • Article
    | Open Access

    How the brain represents 3D space is poorly understood but important for understanding spatial cognition. Here the authors record place cells in rats climbing through a 3D environment and report that they represent this space with 3D fields that are elongated along the axes of the environment and encode the vertical dimension less accurately.

    • Roddy M. Grieves
    • , Selim Jedidi-Ayoub
    • , Karyna Mishchanchuk
    • , Anyi Liu
    • , Sophie Renaudineau
    •  & Kate J. Jeffery
  • Article
    | Open Access

    Aberrant tissue repair may result in heterotopic ossification (HO), but how this process is regulated by local inflammatory responses is still unclear. Here the authors show, using a mouse burn/trauma model, that TGFβ-producing monocytes/macrophages at the injury site contribute to HO induction, while CD47 activation helps antagonize this process.

    • Michael Sorkin
    • , Amanda K. Huber
    • , Charles Hwang
    • , William F. Carson IV
    • , Rajasree Menon
    • , John Li
    • , Kaetlin Vasquez
    • , Chase Pagani
    • , Nicole Patel
    • , Shuli Li
    • , Noelle D. Visser
    • , Yashar Niknafs
    • , Shawn Loder
    • , Melissa Scola
    • , Dylan Nycz
    • , Katherine Gallagher
    • , Laurie K. McCauley
    • , Jiajia Xu
    • , Aaron W. James
    • , Shailesh Agarwal
    • , Stephen Kunkel
    • , Yuji Mishina
    •  & Benjamin Levi
  • Perspective
    | Open Access

    Genome-scale engineering requires the integration of a wide range of in silico and in vivo technologies, as well data management procedures and legal infrastructure. Here the authors provide a list of recommendations to address these challenges.

    • Bryan A. Bartley
    • , Jacob Beal
    • , Jonathan R. Karr
    •  & Elizabeth A. Strychalski
  • Article
    | Open Access

    Current cellular rewiring designs are typically tailored to detect single inputs. Here the authors present GEARs that function independently of engineered receptor/reporter systems and directly reroute endogenous signaling pathways to alternative genomic loci using dCas9-directed gene expression.

    • Krzysztof Krawczyk
    • , Leo Scheller
    • , Hyojin Kim
    •  & Martin Fussenegger
  • Article
    | Open Access

    Kras is often mutated in colorectal cancer but how this oncogenic mutation alters signalling pathways globally is undetermined. Here, the authors analyse how this mutation affects protein interaction networks and signal flow showing an extensive re‐wiring of signalling in response to KRas mutation

    • Susan A. Kennedy
    • , Mohamed-Ali Jarboui
    • , Sriganesh Srihari
    • , Cinzia Raso
    • , Kenneth Bryan
    • , Layal Dernayka
    • , Theodosia Charitou
    • , Manuel Bernal-Llinares
    • , Carlos Herrera-Montavez
    • , Aleksandar Krstic
    • , David Matallanas
    • , Max Kotlyar
    • , Igor Jurisica
    • , Jasna Curak
    • , Victoria Wong
    • , Igor Stagljar
    • , Thierry LeBihan
    • , Lisa Imrie
    • , Priyanka Pillai
    • , Miriam A. Lynn
    • , Erik Fasterius
    • , Cristina Al-Khalili Szigyarto
    • , James Breen
    • , Christina Kiel
    • , Luis Serrano
    • , Nora Rauch
    • , Oleksii Rukhlenko
    • , Boris N. Kholodenko
    • , Luis F. Iglesias-Martinez
    • , Colm J. Ryan
    • , Ruth Pilkington
    • , Patrizia Cammareri
    • , Owen Sansom
    • , Steven Shave
    • , Manfred Auer
    • , Nicola Horn
    • , Franziska Klose
    • , Marius Ueffing
    • , Karsten Boldt
    • , David J. Lynn
    •  & Walter Kolch
  • Article
    | Open Access

    Chromosome arm-level aneuploidies (CAAs) are frequently observed in cancer. Here, the authors analyse CAA landscapes across different tumour types, relating these chromosome arm gains and losses to tumour evolution, metastasis, patient survival and response to a range of anti-cancer therapies.

    • Ankit Shukla
    • , Thu H. M. Nguyen
    • , Sarat B. Moka
    • , Jonathan J. Ellis
    • , John P. Grady
    • , Harald Oey
    • , Alexandre S. Cristino
    • , Kum Kum Khanna
    • , Dirk P. Kroese
    • , Lutz Krause
    • , Eloise Dray
    • , J. Lynn Fink
    •  & Pascal H. G. Duijf
  • Article
    | Open Access

    Cellular interactions are a major driver of microbial communities and shown highly variable in strength. Here the authors construct synthetic consortia and mathematical models to elucidate the role of interaction variability in driving ecosystem succession.

    • Feng Liu
    • , Junwen Mao
    • , Wentao Kong
    • , Qiang Hua
    • , Youjun Feng
    • , Rashid Bashir
    •  & Ting Lu
  • Article
    | Open Access

    Accounting for the effects of genetic expression in genome-scale metabolic models is challenging. Here, the authors introduce a model formulation that efficiently simulates thermodynamic-compliant fluxes, enzyme and mRNA concentration levels, allowing omics integration and broad analysis of in silico cellular physiology.

    • Pierre Salvy
    •  & Vassily Hatzimanikatis
  • Article
    | Open Access

    We lack effective treatment for half of children with high-risk neuroblastoma. Here, the authors introduce an algorithm that can predict the effect of interventions on gene expression signatures associated with high disease processes and risk, and identify and validate promising drug targets.

    • Elin Almstedt
    • , Ramy Elgendy
    • , Neda Hekmati
    • , Emil Rosén
    • , Caroline Wärn
    • , Thale Kristin Olsen
    • , Cecilia Dyberg
    • , Milena Doroszko
    • , Ida Larsson
    • , Anders Sundström
    • , Marie Arsenian Henriksson
    • , Sven Påhlman
    • , Daniel Bexell
    • , Michael Vanlandewijck
    • , Per Kogner
    • , Rebecka Jörnsten
    • , Cecilia Krona
    •  & Sven Nelander
  • Article
    | Open Access

    The secretory pathway is used in the production of most biopharmaceuticals, but the associated biosynthetic costs are little understood. Here, the authors integrate the core secretory pathway into genome-scale metabolic models of human, mouse, and CHO cells, enabling in silico analysis.

    • Jahir M. Gutierrez
    • , Amir Feizi
    • , Shangzhong Li
    • , Thomas B. Kallehauge
    • , Hooman Hefzi
    • , Lise M. Grav
    • , Daniel Ley
    • , Deniz Baycin Hizal
    • , Michael J. Betenbaugh
    • , Bjorn Voldborg
    • , Helene Faustrup Kildegaard
    • , Gyun Min Lee
    • , Bernhard O. Palsson
    • , Jens Nielsen
    •  & Nathan E. Lewis
  • Article
    | Open Access

    Feedback mechanisms for synthetic gene circuits are necessary to provide robustness to external perturbations. Here the authors validate a biomolecular controller based on a sigma and anti-sigma factor to achieve stable gene expression in the face of external disturbances in an in vitro synthetic gene circuit.

    • Deepak K. Agrawal
    • , Ryan Marshall
    • , Vincent Noireaux
    •  & Eduardo D Sontag
  • Article
    | Open Access

    Culturing transposon-mutant libraries in pools can mask complex phenotypes. Here the authors present microfluidics mediated droplet Tn-Seq, which encapsulates individual mutants, promotes isolated growth and enables cell-cell interaction analyses.

    • Derek Thibault
    • , Paul A. Jensen
    • , Stephen Wood
    • , Christine Qabar
    • , Stacie Clark
    • , Mara G. Shainheit
    • , Ralph R. Isberg
    •  & Tim van Opijnen
  • Article
    | Open Access

    There are many examples of cell populations exhibiting density-dependent collective oscillatory behaviour. Here, the authors show that sustained collective oscillations emerge when cells anticipate variation in signal and attempt to amplify it, a property that can be linked to adaptation.

    • Shou-Wen Wang
    •  & Lei-Han Tang
  • Article
    | Open Access

    Intermediate transitions between epithelial and mesenchymal states are associated with tumor progression. Here using mass cytometry, Plevritis and colleagues develop a computational framework to resolve and map these trajectories in lung cancer cells and clinical specimens.

    • Loukia G. Karacosta
    • , Benedict Anchang
    • , Nikolaos Ignatiadis
    • , Samuel C. Kimmey
    • , Jalen A. Benson
    • , Joseph B. Shrager
    • , Robert Tibshirani
    • , Sean C. Bendall
    •  & Sylvia K. Plevritis
  • Article
    | Open Access

    Avian influenza A virus (IAV) strains replicate poorly in mammalian hosts, but mechanisms underlying species restriction are incompletely understood. Here, Bogdanow et al. show that avian and mammalian adapted IAV strains have evolved different RNA structure features for regulation of M segment RNA splicing.

    • Boris Bogdanow
    • , Xi Wang
    • , Katrin Eichelbaum
    • , Anne Sadewasser
    • , Immanuel Husic
    • , Katharina Paki
    • , Matthias Budt
    • , Martha Hergeselle
    • , Barbara Vetter
    • , Jingyi Hou
    • , Wei Chen
    • , Lüder Wiebusch
    • , Irmtraud M. Meyer
    • , Thorsten Wolff
    •  & Matthias Selbach