Systems biology articles within Nature Communications

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  • Article
    | Open Access

    Single cell RNA-Seq data can report on cellular types and states, but low signal-to noise and sparse data can make interpretation of cellular state difficult. Here the authors propose a transformation strategy to map RNA-Seq data to biological process activities that are species-agnostic and allow for comparison across species.

    • Hongxu Ding
    • , Andrew Blair
    •  & Joshua M. Stuart

  • Article
    | Open Access

    Osteoarthritis results from the progressive destruction of cartilage matrix. Here, Kim et al. identify tankyrase as a regulator of cartilage matrix anabolism, and find that tankyrase inhibition, by preventing SOX9 PARylation, protects from cartilage destruction in a mouse model of osteoarthritis.

    • Sukyeong Kim
    • , Sangbin Han
    •  & Jin-Hong Kim

  • Article
    | Open Access

    It is difficult to improve the efficacy of oncolytic virotherapy due to immune system responses and limited understanding of population dynamics. Here the authors use synthetic biology gene circuits to control adenoviral replication and release of immunomodulators in hepatocellular carcinoma cells.

    • Huiya Huang
    • , Yiqi Liu
    •  & Zhen Xie

  • Article
    | Open Access

    The complexity of the innate immune response to cancer makes interpretation of large data sets challenging. Here, the authors provide an integrated multi-scale map of signalling networks representing the different immune cells and their interactions and show its utility for data interpretation.

    • Maria Kondratova
    • , Urszula Czerwinska
    •  & Inna Kuperstein

  • Article
    | Open Access

    Immune cells are shaped by the tissue environment, yet the states of healthy human T cells are mainly studied in the blood. Here, the authors perform single cell RNA-seq of T cells from tissues and blood of healthy donors and show its utility as a reference map for comparison of human T cell states in disease.

    • Peter A. Szabo
    • , Hanna Mendes Levitin
    •  & Peter A. Sims

  • Article
    | Open Access

    An understanding of the ancestral state of the neural crest (NC) gene regulatory network (GRN) gives insight into vertebrate evolution. Here, the authors use transcriptomic and chromatin accessibility analyses of the lamprey NC, as well as cross-species enhancer assays, to identify GRN elements conserved throughout vertebrates.

    • Dorit Hockman
    • , Vanessa Chong-Morrison
    •  & Tatjana Sauka-Spengler

  • Article
    | Open Access

    Cell fate commitment is understood in terms of bistable regulatory circuits with hysteresis, but inherent stochasticity in gene expression is incompatible with hysteresis. Here, the authors quantify how, under slow dynamics, the dependency of the non-stationary solutions on the initial state of the cells can lead to transient hysteresis.

    • M. Pájaro
    • , I. Otero-Muras
    •  & A. A. Alonso

  • Article
    | Open Access

    How receptor localization affects morphogen gradient formation during embryonic development is unclear. Here, the authors study the relationship between the BMP gradient, receptor localization, and compartmentalized geometry in the early mouse embryo, using experimental data and computational simulation.

    • Zhechun Zhang
    • , Steven Zwick
    •  & Sharad Ramanathan

  • Article
    | Open Access

    Interactions between metabolites and transcription factors are known to control gene expression but analyzing these events at genome-scale is challenging. Here, the authors integrate dynamic metabolome and transcriptome data from E.coli to predict regulatory metabolite-transcription factor interactions.

    • Martin Lempp
    • , Niklas Farke
    •  & Hannes Link

  • Article
    | Open Access

    Epistasis underlies the complexity of genotype-phenotype maps. Here, the authors analyze 8,192 mutants that link two phenotypically distinct variants of the Entacmaea quadricolor fluorescent protein, and show the existence, but also the sparsity, of high-order epistatic interactions.

    • Frank J. Poelwijk
    • , Michael Socolich
    •  & Rama Ranganathan

  • Article
    | Open Access

    TDP43 aggregates are a hallmark of amyotrophic lateral sclerosis. By using deep mutagenesis to measure the toxicity of more than 50,000 mutations in the prion domain of TDP43, the authors conclude that mutations that increase toxicity promote formation of liquid-like condensates, while aggregation of TDP43 is protective for the cell.

    • Benedetta Bolognesi
    • , Andre J. Faure
    •  & Ben Lehner

  • Article
    | Open Access

    Low frequency coding single-nucleotide variants (SNVs) are predicted to disproportionately affect protein function. Here, the authors evaluate 2,009 missense SNVs across 2,185 protein-protein interactions using yeast two-hybrid and protein complementation assays and find that disruptive SNVs often occur in disease-associated genes.

    • Robert Fragoza
    • , Jishnu Das
    •  & Haiyuan Yu

  • Article
    | Open Access

    Crosstalk between genetic circuits is a major challenge for engineering sophisticated networks. Here the authors design networks that compensate for crosstalk by integrating, not insulating, pathways.

    • Isaak E. Müller
    • , Jacob R. Rubens
    •  & Timothy K. Lu

  • Article
    | Open Access

    The relationship between metabolomic and behavioral changes is not well understood. Here, the authors analyze metabolome changes in D. melanogaster heads and bodies during hunger and satiety, and develop the Flyscape tool to visualize the resulting metabolic networks and integrate them with other omics data.

    • Daniel Wilinski
    • , Jasmine Winzeler
    •  & Monica Dus

  • Article
    | Open Access

    Linear controllability theories have stimulated research on control of complex networks. Here the authors investigate the concordance between linear and nonlinear approaches in ranking the importance of nodes in nonlinear networks, and conclude that linear controllability may not be applicable.

    • Junjie Jiang
    •  & Ying-Cheng Lai

  • Article
    | Open Access

    Natural killer (NK) cells are important innate immune cells with diverse functions. Here the authors use single-cell RNA-sequencing of purified human bone marrow and peripheral blood NK cells to define five populations of NK cells with distinct transcriptomic profile to further our understanding of NK development and heterogeneity.

    • Chao Yang
    • , Jason R. Siebert
    •  & Subramaniam Malarkannan

  • Article
    | Open Access

    Non-additive genetic interactions are plastic and can complicate genetic prediction. Here, using deep mutagenesis of the lambda repressor, Li et al. reveal that changes in gene expression can alter the strength and direction of genetic interactions between mutations in many genes and develop mathematical models for predicting them.

    • Xianghua Li
    • , Jasna Lalić
    •  & Ben Lehner

  • Article
    | Open Access

    Titers of monoterpenoids production in yeast are low due to the fact that the geranyl diphosphate (GPP)-based pathway can redirect metabolic fluxes to growth. Here, the authors build an orthogonal pathway by selecting the cis isomer of GPP as an alternative precursor and achieve high titer monoterpene production.

    • Codruta Ignea
    • , Morten H. Raadam
    •  & Sotirios C. Kampranis

  • Article
    | Open Access

    Current flux rewiring technologies in metabolic engineering are mainly transcriptional regulation. Here, the authors build two sets of controllable protein units using engineered viral proteases and proteolytic signals, and utilize for increasing titers of shikimate and D-xylonate in E. coli.

    • Cong Gao
    • , Jianshen Hou
    •  & Liming Liu

  • Article
    | Open Access

    Studying how genetic variants in different genes interact and their combinatorial output is experimentally and analytically challenging. Here, the authors quantify the effects of more than 5000 mutation pairs in the yeast GAL regulatory system, finding that many combinations can be predicted with statistical models.

    • Aaron M. New
    •  & Ben Lehner

  • Article
    | Open Access

    Model-based centralization schemes, though able to quantify locomotion control in animals and bio-inspired robots, are limited to specific systems. Here, the authors report a generalized information-based centralization scheme that unifies existing models and can be applied to different systems.

    • Izaak D. Neveln
    • , Amoolya Tirumalai
    •  & Simon Sponberg

  • Article
    | Open Access

    Gene activation requires an increase of successful initiation events. Here, by employing a genome-wide kinetic analysis of transcription, the authors showed that gene activation generally requires a decrease in RNA Polymerase II (Pol II) promoter-proximal pausing while transcription of enhancer elements is not limited by Pol II pausing.

    • Saskia Gressel
    • , Björn Schwalb
    •  & Patrick Cramer

  • Article
    | Open Access

    Microbial respiration releases carbon from the soil. Here, the authors estimate bacterial carbon use efficiency in soils for over 200 species using constraint-based modeling, incorporate the values into an ecosystem model, and find that shifts in community composition may impact carbon storage.

    • Mustafa Saifuddin
    • , Jennifer M. Bhatnagar
    •  & Adrien C. Finzi

  • Article
    | Open Access

    Identification of disease modules in the human interactome can guide more efficacious therapeutic selections. Here, the authors introduce a network-based methodology to identify individualized disease modules by mapping patients’ DNA and RNA sequencing profiles to the interactome, enabling prediction of cancer type-specific drug responses.

    • Feixiong Cheng
    • , Weiqiang Lu
    •  & Joseph Loscalzo

  • Perspective
    | Open Access

    No effective therapies exist for dry age-related macular degeneration. In this perspective, the authors propose that research should emphasize system biology approaches that integrate various ‘omics’ data into mathematical models to establish pathogenic mechanisms on which to design novel treatments, and identify biomarkers that predict disease progression and therapeutic response.

    • James T. Handa
    • , Cathy Bowes Rickman
    •  & Lindsay A. Farrer

  • Article
    | Open Access

    The fraction of protein-protein interactions (PPIs) that can be disrupted without fitness effect is unknown. Here, the authors model how disease-causing mutations and common mutations carried by healthy people perturb the interactome, and estimate that <20% of human PPIs are completely dispensable.

    • Mohamed Ghadie
    •  & Yu Xia

  • Article
    | Open Access

    Quantifying the effects of noise in gene expression is difficult since noise and mean expression are coupled. Here the authors determine fitness landscapes in mean-noise expression space to uncouple these two parameters and show that changes in noise and mean expression are similarly detrimental to fitness.

    • Jörn M. Schmiedel
    • , Lucas B. Carey
    •  & Ben Lehner

  • Article
    | Open Access

    Membrane proteins have been implicated in cancers, but studying the downstream effects of their perturbation remains challenging. Here, the authors map the membrane protein-regulated network of 15 cancers, a resource for prognostic biomarker development and druggable target identification.

    • Chun-Yu Lin
    • , Chia-Hwa Lee
    •  & Jinn-Moon Yang

  • Article
    | Open Access

    Bacillus subtilis has complex spatial and temporal gene expression patterns but currently lacks optogenetic tools to explore these processes. Here the authors import and debug a cyanobacterial green light sensor pathway and show that it enables precise optical control of gene expression.

    • Sebastian M. Castillo-Hair
    • , Elliot A. Baerman
    •  & Jeffrey J. Tabor

  • Article
    | Open Access

    Construction of yeast libraries is time-consuming, costly and limited to the genetic background of the chosen strain. Here the authors present CASTLING which uses CRISPR-Cas12a and oligonucleotide pools to rapidly generate pooled libraries with large insertions such as fluorescent protein tags.

    • Benjamin C. Buchmuller
    • , Konrad Herbst
    •  & Michael Knop

  • Article
    | Open Access

    Light-sheet microscopes are increasingly used for imaging cleared tissues, but have imposed constraints on sample geometries and protocols. Here the authors present a multi-immersion open-top light-sheet microscope to overcome these limitations and enable high-throughput imaging of samples processed with various clearing protocols.

    • Adam K. Glaser
    • , Nicholas P. Reder
    •  & Jonathan T. C. Liu

  • Article
    | Open Access

    The role of gene expression noise in the evolution of drug resistance in mammalian cells is unclear. Here, by uncoupling noise from mean expression of a drug resistance gene in CHO cells the authors show that noisy expression aids adaptation to high drug levels, but delays it at low drug levels.

    • Kevin S. Farquhar
    • , Daniel A. Charlebois
    •  & Gábor Balázsi

  • Article
    | Open Access

    The type II nuclear receptors (NRs) and the retinoid X receptor (RXR) form heterodimeric transcription factors to regulate development, metabolism, and inflammation. Here the authors employ protein-binding microarrays to comprehensively analyze the DNA binding of 12 NR:RXRα heterodimers, and report promiscuous NR-DNA binding.

    • Ashley Penvose
    • , Jessica L. Keenan
    •  & Trevor Siggers

  • Article
    | Open Access

    In asexual populations selection at different genomic loci can interfere with each other. Here, using a biophysical model of molecular evolution the authors show that interference results in long-term degradation of molecular function, an effect that strongly depends on genome size.

    • Torsten Held
    • , Daniel Klemmer
    •  & Michael Lässig

  • Article
    | Open Access

    Adoption of DNA as a data storage medium could be accelerated with specialized synthesis processes and codecs. The authors describe TdT-mediated DNA synthesis in which data is stored in transitions between non-identical nucleotides and the use of synchronization markers to provide error tolerance.

    • Henry H. Lee
    • , Reza Kalhor
    •  & George M. Church

  • Article
    | Open Access

    Polycomb and Trithorax group proteins regulate silent and active gene expression states, but also allow poised states in pluripotent cells. Here the authors present a mathematical model that integrates data on Polycomb/ Trithorax biochemistry into a single coherent framework which predicts that poised chromatin is not bivalent as previously proposed, but is bistable, meaning that the system switches frequently between stable active and silent states.

    • Kim Sneppen
    •  & Leonie Ringrose

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