Systems analysis

  • Article
    | Open Access

    OTULIN is a deubiquitinase for linear ubiquitin chains. Here the authors show, using genetic mouse models and single-cell RNA-sequencing, that deficiency of OTULIN in keratinocytes causes skin inflammation and verrucous carcinoma via the induction of keratinocyte death, thereby implicating a function of OTULIN in keratinocyte homeostasis.

    • Esther Hoste
    • , Kim Lecomte
    •  & Geert van Loo
  • Article
    | Open Access

    Regulatory T (Treg) cells are important modulators of the tumor microenvironment. Here the authors perform transcriptome profiling of immune cells from patients with renal clear cell carcinoma to find a Treg signature that correlates with poorer prognosis, with CD177 being implicated as the main mediator for related alterations in Treg activity and tumor outcome.

    • Myung-Chul Kim
    • , Nicholas Borcherding
    •  & Weizhou Zhang
  • Article
    | Open Access

    Transcription in archaea is known to be regulated through the recruitment of RNA polymerase to promoters. Here, the authors show that the archaeon Saccharolobus solfataricus regulates transcription globally through a rate-limiting promoter-proximal elongation step.

    • Fabian Blombach
    • , Thomas Fouqueau
    •  & Finn Werner
  • Article
    | Open Access

    Complex biomolecular networks are fundamental to the functioning of living systems, both at the cellular level and beyond. In this paper, the authors develop a systems framework to elucidate the interplay of networks and the spatial localisation of network components.

    • Govind Menon
    •  & J. Krishnan
  • Article
    | Open Access

    Multisystem inflammatory syndrome in children (MIS-C) onsets in COVID-19 patients with manifestations similar to Kawasaki disease (KD). Here the author probe the peripheral blood transcriptome of MIS-C patients to find signatures related to natural killer (NK) cell activation and CD8+ T cell exhaustion that are shared with KD patients.

    • Noam D. Beckmann
    • , Phillip H. Comella
    •  & Alexander W. Charney
  • Article
    | Open Access

    COVID-19 is a critical public health threat, but molecular characterizations of patients’ immunity is still lacking. Here the authors collected blood from patients with various disease severity, and prefiltered to exclude selected comorbidity, to obtain genomic, transcriptomic, proteomic, metabolomic and lipidomic profiles to report a trans-omics landscape.

    • Peng Wu
    • , Dongsheng Chen
    •  & Gang Chen
  • Article
    | Open Access

    Longitudinal multi-omics measurements are highly valuable in studying heterogeneity in health and disease phenotypes. Here, the authors apply Pareto Task Inference to analyze the clinical lab tests of 3094 individuals and find three wellness states, and one aberrant health state defining this cohort.

    • Anat Zimmer
    • , Yael Korem
    •  & Nathan D. Price
  • Article
    | Open Access

    Some patients with COVID-19 fail to clear the viral infection quickly, yet our understanding for the underlying immune characteristics is still lacking. Here the authors use single-cell RNA sequencing and other data form such patients to show that persistent infection is associated with immune suppression and reduced expression of ribosomal protein genes.

    • Bin Yang
    • , Junpeng Fan
    •  & Chaoyang Sun
  • Article
    | Open Access

    Mucosal-associated invariant T (MAIT) cells are key in immunity and diseases, but how their effector polarization is controlled is still unclear. Here, the authors show that an IL-1β/IL-23/mTORC2 axis is essential for the induction of IL-17-producing MAIT17, while an IL-2/IL-15/mTORC1 axis is important for the homeostasis of IFN-γ-producing MAIT1.

    • Huishan Tao
    • , Yun Pan
    •  & Xiao-Ping Zhong
  • Article
    | Open Access

    Crohn’s disease results from transmural inflammation in the gut, but analyses of local immune populations are still lacking. Here, the authors show, by combining multiple single-cell approaches, that intraepithelial and lamina propria T cells are heterogenous, show unique phenotypes, and exhibit altered subsets upon inflammation.

    • Natalia Jaeger
    • , Ramya Gamini
    •  & Marco Colonna
  • Article
    | Open Access

    The thymus supports T cell immunity by providing the environment for thymocyte differentiation. Here the authors profile human thymic stroma at the single cell level, identifying ionocytes as a new medullary population and defining tissue specific antigen expression in multiple stromal cell types.

    • Jhoanne L. Bautista
    • , Nathan T. Cramer
    •  & Audrey V. Parent
  • Article
    | Open Access

    Macrophages can be polarized by in vitro culture stimuli into M1 or M2 cells, but microenvironments in vivo are more complex. Here the authors analyze cultured macrophages stimulated with a combination of M1 and M2 stimuli by single-cell RNA sequencing, machine learning, and single-cell secretion profiling to show a surprising level of heterogeneity of response.

    • Andrés R. Muñoz-Rojas
    • , Ilana Kelsey
    •  & Kathryn Miller-Jensen
  • Article
    | Open Access

    Anecdotal reports suggest potential severity and outcome differences between sexes following infection by SARS-CoV-2. Here, the authors perform meta-analyses of more than 3 million cases collected from global public data to demonstrate that male patients with COVID-19 are 3 times more likely to require intensive care, and have ~40% higher death rate.

    • Hannah Peckham
    • , Nina M. de Gruijter
    •  & Claire T. Deakin
  • Article
    | Open Access

    Innate-like T cells such as invariant natural killer T (iNKT) and mucosal-associated invariant T (MAIT) cells both develop in the thymus. Here the authors use single-cell RNA sequencing to show that mouse iNKT and MAIT share components of developmental regulation, with a transcription factor, Hivep3, implicated for the maturation of both cell types.

    • S. Harsha Krovi
    • , Jingjing Zhang
    •  & Laurent Gapin
  • Article
    | Open Access

    Bacterial vaginosis (BV) is typically caused by a shift in the vaginal microbiota from a Lactobacillus-dominant community to one colonised by strains of Gardenerella vaginalis and treatment with the antibiotic metronidazole (MNZ) often results in failure and recurrence. Here, the authors use modelling and in vitro assays to show that sequestration of MNZ by Lactobacillus is critical in reducing efficacy and women with a higher pre-treatment Lactobacillus/Gardnerella ratio are more likely to recur.

    • Christina Y. Lee
    • , Ryan K. Cheu
    •  & Kelly B. Arnold
  • Article
    | Open Access

    Neuron-astrocyte communication plays a key role in pathophysiology, however systematic approaches to unveil it are limited. Here, the authors propose SEARCHIN, a multi-modal integrated workflow, as a tool to identify cross-compartment ligand-receptor interactions, applied to ALS models.

    • Vartika Mishra
    • , Diane B. Re
    •  & Serge Przedborski
  • Article
    | Open Access

    ATP drives most cellular processes, although ATP production and consumption levels during mitosis remain unreported. Here, the authors combine metabolic measurements and modeling to quantify ATP levels and synthesis dynamics, revealing that ATP synthesis and consumption are lowered during mitosis.

    • Joon Ho Kang
    • , Georgios Katsikis
    •  & Teemu P. Miettinen
  • Article
    | Open Access

    Arterial macrophages develop from either yolk sac or bone marrow progenitors. Here, the author show that ageing-induced reduction of arterial macrophages is not replenished by bone marrow-derived cells, but under inflammatory conditions circulating monocytes are recruited to maintain homeostasis, while arterial macrophages of yolk sac origin carry out tissue repair.

    • Tobias Weinberger
    • , Dena Esfandyari
    •  & Christian Schulz
  • Article
    | Open Access

    The developmental origins and functions of testis macrophages remain incompletely characterized. Here, the authors show, using histology, high-dimensional mass cytometry and cell fate-mapping data, that interstitial and peritubular macrophages originate from distinct precursors and contribute distinctly to spermatogenesis.

    • Emmi Lokka
    • , Laura Lintukorpi
    •  & Marko Salmi
  • 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
    •  & 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
    •  & Simon Kasif
  • 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
    •  & Gosia Trynka
  • 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
    •  & Benjamin Levi
  • 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
    •  & Matthias Selbach
  • 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

    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

    The white pulp of spleen is an important immune structure dynamically modulated during development and immune responses. Here the authors define, using multi-color lineage tracing and single-cell transcriptome analysis, the subset distribution and differentiation trajectory of fibroblastic reticular cells to serve structural insights for splenic white pulps.

    • Hung-Wei Cheng
    • , Lucas Onder
    •  & Burkhard Ludewig
  • Article
    | Open Access

    Computational protein-protein interaction (PPI) prediction has the potential to complement experimental efforts to map interactomes. Here, the authors show that proteins tend to interact if one is similar to the other’s partners and that PPI prediction based on this principle is highly accurate.

    • István A. Kovács
    • , Katja Luck
    •  & Albert-László Barabási
  • Article
    | Open Access

    Genome-reduced bacteria often show impaired growth under laboratory conditions. Here the authors use adaptive laboratory evolution to optimise growth performance and show transcriptome and translatome-wide remodeling of the organism.

    • Donghui Choe
    • , Jun Hyoung Lee
    •  & Byung-Kwan Cho
  • Article
    | Open Access

    Tissue-resident macrophages are highly specialized phagocytes that serve multiple functions. Here, using high-dimension analyses and fate-mapping experiments, the authors show that fetal liver-derived macrophages dominate the mammary gland in neonatal and adult, and display characteristic phenotypes and functions.

    • Norma Jäppinen
    • , Inês Félix
    •  & Marko Salmi
  • Article
    | Open Access

    Tumours of different tissues can show similarities in genomic alterations. Here, the authors combine tumour transcriptome and protein interaction data in a network-based analysis of 11 tumours types, and identify clusters of tumours with specific signatures for multi-tumour drug targeting and survival prognosis.

    • Ítalo Faria do Valle
    • , Giulia Menichetti
    •  & Daniel Remondini
  • Article
    | Open Access

    B-cell development is tightly regulated by transcription programs that are coordinated by transcription factors (TF) and locus accessibility. Here the authors show that, in mice and humans, the epigenetic reader BRWD1 inhibits and promotes the accessibility of enhancers for early and late B lymphopoiesis, respectively.

    • Malay Mandal
    • , Mark Maienschein-Cline
    •  & Marcus R. Clark
  • Article
    | Open Access

    Finding one’s way to a food source along a complex gradient is central to survival for many animals. Here, the authors report that in C. elegans, the distinct response dynamics of two sensory neurons to odor gradients can support a navigation model more efficient than the biased-random walk.

    • Eyal Itskovits
    • , Rotem Ruach
    •  & Alon Zaslaver
  • Article
    | Open Access

    Diatoms account for 40% of marine primary production and their sensitivity to ocean acidification could have ecosystem-wide consequences. Here, the authors developed and applied a stress test, demonstrating that resilience of diatoms increases significantly in ocean acidification conditions.

    • Jacob J. Valenzuela
    • , Adrián López García de Lomana
    •  & Nitin S. Baliga
  • Article
    | Open Access

    Nodes with high centrality in protein–protein interaction (PPI) networks are known to be essential in some organisms. Here, the authors in contrast find that in the interactome of A. thaliana central nodes are enriched in conditional and immune phenotypes and are preferred targets of pathogens.

    • Hadia Ahmed
    • , T. C. Howton
    •  & M. Shahid Mukhtar
  • Article
    | Open Access

    Single cell analysis provides insight into cell states and transitions, but to interpret the data, improved algorithms are needed. Here, the authors present CellRouter as a method to analyse single-cell trajectories from RNA-sequencing data, and provide insight into erythroid, myeloid and lymphoid differentiation.

    • Edroaldo Lummertz da Rocha
    • , R. Grant Rowe
    •  & George Q. Daley
  • Article
    | Open Access

    Cancer is caused by accumulating genetic mutations. Here, the authors investigate the cooperative effect of these mutations in colorectal cancer patients and identify a giant cluster of mutation-propagating modules that undergoes percolation transition during tumorigenesis.

    • Dongkwan Shin
    • , Jonghoon Lee
    •  & Kwang-Hyun Cho
  • Article
    | Open Access

    Fast-growing bacteria produce many proteins in excess of what seems optimal for exponential growth. Here, the authors present a mathematical model and experimental evidence supporting that this overexpression serves as a strategic reserve to quickly meet demand upon sudden improvement in growth conditions.

    • Matteo Mori
    • , Severin Schink
    •  & Terence Hwa
  • Article
    | Open Access

    The contribution of metabolic pathways to protein secretion is largely unknown. Here, the authors find conserved metabolic patterns in yeast by examining genome-wide transcriptional responses in high protein secretion mutants and reveal critical factors that can be tuned for efficient protein secretion.

    • Mingtao Huang
    • , Jichen Bao
    •  & Jens Nielsen
  • Article
    | Open Access

    High-grade serous ovarian cancers (HGS-OvCa) frequently develop chemotherapy resistance. Here, the authors through a systematic analysis of proteomic and drug response data of 14 HGS-OvCa PDXs demonstrate that targeting apoptosis regulators can improve response of these tumors to inhibitors of the PI3K/mTOR pathway.

    • Ioannis K. Zervantonakis
    • , Claudia Iavarone
    •  & Joan S. Brugge
  • Article
    | Open Access

    Metabolites act as enzyme inhibitors, but their global impact on metabolism has scarcely been considered. Here, the authors generate a human genome-wide metabolite-enzyme inhibition network, and find that inhibition occurs largely due to limited structural diversity of metabolites, leading to a global constraint on metabolism which subcellular compartmentalization minimizes.

    • Mohammad Tauqeer Alam
    • , Viridiana Olin-Sandoval
    •  & Markus Ralser