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PLOS Biology: New Articles

  • <i>EZH2</i> mutations increase the heterogeneity of chromatin states in lymphoma

    by Daniel Holoch, Raphaël Margueron

    A recent study in PLoS Biology used simultaneous measurements of histone modifications in single cells to reveal that EZH2 gain-of-function mutations profoundly reprogram chromatin states in B-cell lymphoma, while also increasing their cell–cell heterogeneity. This Primer discusses a recent study using simultaneous measurements of histone modifications in single cells to reveal that EZH2 gain-of-function mutations profoundly reprogram chromatin states in B-cell lymphoma, while also increasing their cell-cell heterogeneity.

  • Regulation to function: A computational approach to specialized metabolism

    by Justin R. Nodwell

    Despite a century of use in drug discovery, specialized metabolism continues to churn out astonishing discoveries. A new study in PLOS Biology uses a novel computational approach to uncover previously unknown functions of a compound produced by Streptomyces coelicolor. Despite a century of use in drug discovery, specialized metabolism continues to churn out astonishing discoveries. This primer explores a new study in PLOS Biology that uses a novel computational approach to uncover previously unknown functions of a compound produced by Streptomyces coelicolor.

  • Global siRNA screen identifies human host factors critical for SARS-CoV-2 replication and late stages of infection

    by Xin Yin, Yuan Pu, Shuofeng Yuan, Lars Pache, Christopher Churas, Stuart Weston, Laura Riva, Lacy M. Simons, William J. Cisneros, Thomas Clausen, Grace Biddle, Simon Doss-Gollin, Meagan Deming, Paul D. De Jesus, Ha Na Kim, Daniel Fuentes, John M. Whitelock, Jeffrey D. Esko, Megan S. Lord, Ignacio Mena, Adolfo García-Sastre, Judd F. Hultquist, Matthew B. Frieman, Trey Ideker, Dexter Pratt, Laura Martin-Sancho, Sumit K. Chanda

    Defining the subset of cellular factors governing SARS-CoV-2 replication can provide critical insights into viral pathogenesis and identify targets for host-directed antiviral therapies. While a number of genetic screens have previously reported SARS-CoV-2 host dependency factors, most of these approaches relied on utilizing pooled genome-scale CRISPR libraries, which are biased toward the discovery of host proteins impacting early stages of viral replication. To identify host factors involved throughout the SARS-CoV-2 infectious cycle, we conducted an arrayed genome-scale siRNA screen. Resulting data were integrated with published functional screens and proteomics data to reveal (i) common pathways that were identified in all OMICs datasets—including regulation of Wnt signaling and gap junctions, (ii) pathways uniquely identified in this screen—including NADH oxidation, or (iii) pathways supported by this screen and proteomics data but not published functional screens—including arachionate production and MAPK signaling. The identified proviral host factors were mapped into the SARS-CoV-2 infectious cycle, including 32 proteins that were determined to impact viral replication and 27 impacting late stages of infection, respectively. Additionally, a subset of proteins was tested across other coronaviruses revealing a subset of proviral factors that were conserved across pandemic SARS-CoV-2, epidemic SARS-CoV-1 and MERS-CoV, and the seasonal coronavirus OC43-CoV. Further studies illuminated a role for the heparan sulfate proteoglycan perlecan in SARS-CoV-2 viral entry and found that inhibition of the non-canonical NF-kB pathway through targeting of BIRC2 restricts SARS-CoV-2 replication both in vitro and in vivo. These studies provide critical insight into the landscape of virus–host interactions driving SARS-CoV-2 replication as well as valuable targets for host-directed antivirals.

  • A unified framework to model synaptic dynamics during the sleep–wake cycle

    by Fukuaki L. Kinoshita, Rikuhiro G. Yamada, Koji L. Ode, Hiroki R. Ueda

    Understanding synaptic dynamics during the sleep–wake cycle in the cortex is crucial yet remains controversial. The synaptic homeostasis hypothesis (SHY) suggests synaptic depression during non-rapid eye movement (NREM) sleep, while other studies report synaptic potentiation or synaptic changes during NREM sleep depending on activities in wakefulness. To find boundary conditions between these contradictory observations, we focused on learning rules and firing patterns that contribute to the synaptic dynamics. Using computational models considering mammalian cortical neurons, we found that under Hebbian and spike-timing dependent plasticity (STDP), wake-like firing patterns decrease synaptic weights, while sleep-like patterns strengthen synaptic weights. We refer to this tendency as Wake Inhibition and Sleep Excitation (WISE). Conversely, under Anti-Hebbian and Anti-STDP, synaptic depression during NREM sleep was observed, aligning with the conventional synaptic homeostasis hypothesis. Moreover, synaptic changes depended on firing rate differences between NREM sleep and wakefulness. We provide a unified framework that could explain synaptic homeodynamics under the sleep–wake cycle.

  • Genome mining based on transcriptional regulatory networks uncovers a novel locus involved in desferrioxamine biosynthesis

    by Hannah E. Augustijn, Zachary L. Reitz, Le Zhang, Jeanine A. Boot, Somayah S. Elsayed, Gregory L. Challis, Marnix H. Medema, Gilles P. van Wezel

    Bacteria produce a plethora of natural products that are in clinical, agricultural and biotechnological use. Genome mining has uncovered millions of biosynthetic gene clusters (BGCs) that encode their biosynthesis, the vast majority of them lacking a clear product or function. Thus, a major challenge is to predict the bioactivities of the molecules these BGCs specify, and how to elicit their expression. Here, we present an innovative strategy whereby we harness the power of regulatory networks combined with global gene expression patterns to predict BGC functions. Bioinformatic analysis of all genes predicted to be controlled by the iron master regulator DmdR1 combined with co-expression data, led to identification of the novel operon desJGH that plays a key role in the biosynthesis of the iron overload drug desferrioxamine (DFO) B in Streptomyces coelicolor. Deletion of either desG or desH strongly reduces the biosynthesis of DFO B, while that of DFO E is enhanced. DesJGH most likely act by changing the balance between the DFO precursors. Our work shows the power of harnessing regulation-based genome mining to functionally prioritize BGCs, accelerating the discovery of novel bioactive molecules.