Journal article Open Access

Synthetic control systems for high performance gene expression in mammalian cells

Lillccci, Gabriele; Benenson, Yaakov; Khammash, Mustafa


MARC21 XML Export

<?xml version='1.0' encoding='UTF-8'?>
<record xmlns="http://www.loc.gov/MARC21/slim">
  <leader>00000nam##2200000uu#4500</leader>
  <controlfield tag="005">20200120125221.0</controlfield>
  <controlfield tag="001">2668750</controlfield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland</subfield>
    <subfield code="a">Benenson, Yaakov</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland</subfield>
    <subfield code="0">(orcid)0000-0002-4855-9220</subfield>
    <subfield code="a">Khammash,  Mustafa</subfield>
  </datafield>
  <datafield tag="856" ind1="4" ind2=" ">
    <subfield code="s">1197457</subfield>
    <subfield code="z">md5:2ca322a6e2f214f1e028231964ed4d2e</subfield>
    <subfield code="u">https://zenodo.org/record/2668750/files/Lillacci et al NAR 2018.pdf</subfield>
  </datafield>
  <datafield tag="542" ind1=" " ind2=" ">
    <subfield code="l">open</subfield>
  </datafield>
  <datafield tag="260" ind1=" " ind2=" ">
    <subfield code="c">2018-10-12</subfield>
  </datafield>
  <datafield tag="909" ind1="C" ind2="O">
    <subfield code="p">openaire</subfield>
    <subfield code="p">user-cosy-bio</subfield>
    <subfield code="o">oai:zenodo.org:2668750</subfield>
  </datafield>
  <datafield tag="909" ind1="C" ind2="4">
    <subfield code="c">9855-9863</subfield>
    <subfield code="n">18</subfield>
    <subfield code="p">Nucleic Acids Research</subfield>
    <subfield code="v">46</subfield>
  </datafield>
  <datafield tag="100" ind1=" " ind2=" ">
    <subfield code="u">Synthetic control systems for high performance gene expression in mammalian cells</subfield>
    <subfield code="0">(orcid)0000-0002-5162-1750</subfield>
    <subfield code="a">Lillccci, Gabriele</subfield>
  </datafield>
  <datafield tag="245" ind1=" " ind2=" ">
    <subfield code="a">Synthetic control systems for high performance gene expression in mammalian cells</subfield>
  </datafield>
  <datafield tag="980" ind1=" " ind2=" ">
    <subfield code="a">user-cosy-bio</subfield>
  </datafield>
  <datafield tag="536" ind1=" " ind2=" ">
    <subfield code="c">743269</subfield>
    <subfield code="a">Cybergenetics: Theory and Design Tools for Biomolecular Control Systems</subfield>
  </datafield>
  <datafield tag="536" ind1=" " ind2=" ">
    <subfield code="c">766840</subfield>
    <subfield code="a">Control Engineering of Biological Systems for Reliable Synthetic Biology Applications</subfield>
  </datafield>
  <datafield tag="540" ind1=" " ind2=" ">
    <subfield code="u">https://creativecommons.org/licenses/by/4.0/legalcode</subfield>
    <subfield code="a">Creative Commons Attribution 4.0 International</subfield>
  </datafield>
  <datafield tag="650" ind1="1" ind2="7">
    <subfield code="a">cc-by</subfield>
    <subfield code="2">opendefinition.org</subfield>
  </datafield>
  <datafield tag="520" ind1=" " ind2=" ">
    <subfield code="a">&lt;p&gt;&lt;strong&gt;Abstract&lt;/strong&gt;&lt;/p&gt;

&lt;p&gt;Tunable induction of gene expression is an essential tool in biology and biotechnology. In spite of that, current induction systems often exhibit unpredictable behavior and performance shortcomings, including high sensitivity to transactivator dosage and plasmid take-up variation, and excessive consumption of cellular resources. To mitigate these limitations, we introduce here a novel family of gene expression control systems of varying complexity with significantly enhanced performance. These include: (i) an incoherent feedforward circuit that exhibits output tunability and robustness to plasmid take-up variation; (ii) a negative feedback circuit that reduces burden and provides robustness to transactivator dosage variability; and (iii) a new hybrid circuit integrating negative feedback and incoherent feedforward that combines the benefits of both. As with endogenous circuits, the complexity of our genetic controllers is not gratuitous, but is the necessary outcome of more stringent performance requirements. We demonstrate the benefits of these controllers in two applications. In a culture of CHO cells for protein manufacturing, the circuits result in up to a 2.6-fold yield improvement over a standard system. In human-induced pluripotent stem cells they enable precisely regulated expression of an otherwise poorly tolerated gene of interest, resulting in a significant increase in the viability of the transfected cells.&lt;/p&gt;</subfield>
  </datafield>
  <datafield tag="024" ind1=" " ind2=" ">
    <subfield code="a">10.1093/nar/gky795</subfield>
    <subfield code="2">doi</subfield>
  </datafield>
  <datafield tag="980" ind1=" " ind2=" ">
    <subfield code="a">publication</subfield>
    <subfield code="b">article</subfield>
  </datafield>
</record>
26
17
views
downloads
Views 26
Downloads 17
Data volume 20.4 MB
Unique views 26
Unique downloads 17

Share

Cite as