Journal article Open Access

Characterization and mitigation of gene expression burden in mammalian cells

Frei, Timothy; Cella, Federica; Tedeschi, Fabiana; Gutiérrez, Joaquín; Stan, Guy-Bart; Khammash, Mustafa; Siciliano, Velia


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  <identifier identifierType="URL">https://zenodo.org/record/4823156</identifier>
  <creators>
    <creator>
      <creatorName>Frei, Timothy</creatorName>
      <givenName>Timothy</givenName>
      <familyName>Frei</familyName>
      <nameIdentifier nameIdentifierScheme="ORCID" schemeURI="http://orcid.org/">0000-0002-4482-519X</nameIdentifier>
      <affiliation>Department of Biosystems Science and Engineering (D-BSSE), ETH Zürich, Mattenstrasse 26, Basel, 4058, Switzerland</affiliation>
    </creator>
    <creator>
      <creatorName>Cella, Federica</creatorName>
      <givenName>Federica</givenName>
      <familyName>Cella</familyName>
      <nameIdentifier nameIdentifierScheme="ORCID" schemeURI="http://orcid.org/">0000-0002-4167-9625</nameIdentifier>
      <affiliation>Istituto Italiano di Tecnologia-IIT, Largo Barsanti e Matteucci, Naples, 80125, Italy University of Genoa, Genoa, 16132, Italy</affiliation>
    </creator>
    <creator>
      <creatorName>Tedeschi, Fabiana</creatorName>
      <givenName>Fabiana</givenName>
      <familyName>Tedeschi</familyName>
      <affiliation>Istituto Italiano di Tecnologia-IIT, Largo Barsanti e Matteucci, Naples, 80125, Italy</affiliation>
    </creator>
    <creator>
      <creatorName>Gutiérrez, Joaquín</creatorName>
      <givenName>Joaquín</givenName>
      <familyName>Gutiérrez</familyName>
      <affiliation>Department of Biosystems Science and Engineering (D-BSSE), ETH Zürich, Mattenstrasse 26, Basel, 4058, Switzerland</affiliation>
    </creator>
    <creator>
      <creatorName>Stan, Guy-Bart</creatorName>
      <givenName>Guy-Bart</givenName>
      <familyName>Stan</familyName>
      <nameIdentifier nameIdentifierScheme="ORCID" schemeURI="http://orcid.org/">0000-0002-5560-902X</nameIdentifier>
      <affiliation>Department of Bioengineering and Centre for Synthetic Biology, Imperial College London, London, SW7 2AZ, UK</affiliation>
    </creator>
    <creator>
      <creatorName>Khammash, Mustafa</creatorName>
      <givenName>Mustafa</givenName>
      <familyName>Khammash</familyName>
      <nameIdentifier nameIdentifierScheme="ORCID" schemeURI="http://orcid.org/">0000-0002-4855-9220</nameIdentifier>
      <affiliation>Department of Biosystems Science and Engineering (D-BSSE), ETH Zürich, Mattenstrasse 26, Basel, 4058, Switzerland</affiliation>
    </creator>
    <creator>
      <creatorName>Siciliano, Velia</creatorName>
      <givenName>Velia</givenName>
      <familyName>Siciliano</familyName>
      <affiliation>Istituto Italiano di Tecnologia-IIT, Largo Barsanti e Matteucci, Naples, 80125, Italy</affiliation>
    </creator>
  </creators>
  <titles>
    <title>Characterization and mitigation of gene expression burden in mammalian cells</title>
  </titles>
  <publisher>Zenodo</publisher>
  <publicationYear>2020</publicationYear>
  <dates>
    <date dateType="Issued">2020-09-15</date>
  </dates>
  <resourceType resourceTypeGeneral="Text">Journal article</resourceType>
  <alternateIdentifiers>
    <alternateIdentifier alternateIdentifierType="url">https://zenodo.org/record/4823156</alternateIdentifier>
  </alternateIdentifiers>
  <relatedIdentifiers>
    <relatedIdentifier relatedIdentifierType="DOI" relationType="IsIdenticalTo">10.1038/s41467-020-18392-x</relatedIdentifier>
    <relatedIdentifier relatedIdentifierType="URL" relationType="IsPartOf">https://zenodo.org/communities/cosy-bio</relatedIdentifier>
  </relatedIdentifiers>
  <rightsList>
    <rights rightsURI="https://creativecommons.org/licenses/by/4.0/legalcode">Creative Commons Attribution 4.0 International</rights>
    <rights rightsURI="info:eu-repo/semantics/openAccess">Open Access</rights>
  </rightsList>
  <descriptions>
    <description descriptionType="Abstract">&lt;p&gt;&lt;strong&gt;Abstract&lt;/strong&gt;&lt;/p&gt;

&lt;p&gt;Despite recent advances in circuit engineering, the design of genetic networks in mammalian cells is still painstakingly slow and fraught with inexplicable failures. Here, we demonstrate that transiently expressed genes in mammalian cells compete for limited transcriptional and translational resources. This competition results in the coupling of otherwise independent exogenous and endogenous genes, creating a divergence between intended and actual function. Guided by a resource-aware mathematical model, we identify and engineer natural and synthetic miRNA-based incoherent feedforward loop (iFFL) circuits that mitigate gene expression burden. The implementation of these circuits features the use of endogenous miRNAs as elementary components of the engineered iFFL device, a versatile hybrid design that allows burden mitigation to be achieved across different cell-lines with minimal resource requirements. This study establishes the foundations for context-aware prediction and improvement of in vivo synthetic circuit performance, paving the way towards more rational synthetic construct design in mammalian cells.&lt;/p&gt;</description>
  </descriptions>
  <fundingReferences>
    <fundingReference>
      <funderName>European Commission</funderName>
      <funderIdentifier funderIdentifierType="Crossref Funder ID">10.13039/501100000780</funderIdentifier>
      <awardNumber awardURI="info:eu-repo/grantAgreement/EC/H2020/766840/">766840</awardNumber>
      <awardTitle>Control Engineering of Biological Systems for Reliable Synthetic Biology Applications</awardTitle>
    </fundingReference>
  </fundingReferences>
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