CaltechAUTHORS
Published December 21, 2022 | Version Published
Journal Article Open

The sound of silence: Transgene silencing in mammalian cell engineering

Creators

  • 1. ROR icon Rice University
  • 2. ROR icon Massachusetts Institute of Technology
  • 3. ROR icon Northwestern University
  • 4. ROR icon University of Southern California
  • 5. ROR icon Stanford University
  • 6. ROR icon University of Illinois Urbana-Champaign
  • 7. ROR icon The Wallace H. Coulter Department of Biomedical Engineering
  • 8. ROR icon University of Utah
  • 9. ROR icon University of California, Los Angeles
  • 10. ROR icon Boston University
  • 11. ROR icon Harvard University
  • 12. ROR icon Broad Institute
  • 13. ROR icon University of Edinburgh
  • 14. ROR icon Imperial College London
  • 15. ROR icon California Institute of Technology
  • 16. ROR icon ETH Zurich
  • 17. ROR icon University of Basel

Abstract

To elucidate principles operating in native biological systems and to develop novel biotechnologies, synthetic biology aims to build and integrate synthetic gene circuits within native transcriptional networks. The utility of synthetic gene circuits for cell engineering relies on the ability to control the expression of all constituent transgene components. Transgene silencing, defined as the loss of expression over time, persists as an obstacle for engineering primary cells and stem cells with transgenic cargos. In this review, we highlight the challenge that transgene silencing poses to the robust engineering of mammalian cells, outline potential molecular mechanisms of silencing, and present approaches for preventing transgene silencing. We conclude with a perspective identifying future research directions for improving the performance of synthetic gene circuits.

Additional Information

Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) Funding for this work was supported in part by the National Institutes of Health grants 1DP2CA250006-01 (T.L.D.), 1R01GM129011 (W.W.W.), R01EB029483 (W.W.W.), 1R01EB026510 (J.N.L.), R21EB030772 (I.B.H.), R35GM143532 (I.B.H.), R35GM143033 (K.E.G.), R35GM138256 (L.M.), 4K00DK126120-03 (J.T.), R01EB029483 (A.S.K.), R35GM128947 (L.B.), R01EB030946 (R.W.), R01EB025256 (R.W.), 1UM1HG009402 (H.Z.), U54DK107965 (H.Z.), R21CA232244 (K.A.H.), 1RC2DK120535-01A1 (J.J.C.), and 1U01 DK 127420-01 (M.B.E.), the National Science Foundation grants CBET-2034495 (L.M.), CBET-2145528 (L.M.), 2141064 (K.S.L.), EF-1921677 (A.S.K.), and EF-2021552 under subaward UWSC10142 (M.B.E.). Further support was also provided by the Biotechnology and Biological Sciences Research Council (BBSRC) BB/S006206/1 (K.P.) and BB/M018040/1 (S.J.R.), ElectroGene 785800 (M.F.), the SNF (M.F.), the Paul Allen Foundation (W.W.W.), AOFSR FA9550-22-1-0316 (K.E.G.), the Wellcome Sanger Institute LEAP 21-275 (L.M.), the Parker Institute for Cancer Immunotherapy (Y.Y.C.), the W.H. Coulter Department of Biomedical Engineering at Emory University (C.E.S.), and the DoD Vannevar Bush Faculty Fellowship N00014-20-1-2825 (A.S.K.). M.B.E. is a Howard Hughes Medical Institute investigator. The authors listed with equal contribution are listed in the author list in alphabetical order.

Conflict of Interest

J.T. and L.B. acknowledge outside interest in Stylus Medicine.

Files

1-s2.0-S2405471222004641-main.pdf

Files (3.8 MB)

Name Size Download all
md5:6eb4cf74d0ded97c1d5f2d8e8b95eccf
3.8 MB Preview Download

Additional details

Identifiers

PMCID
PMC9880859
Eprint ID
119035
Resolver ID
CaltechAUTHORS:20230203-893712500.43
DOI
10.1016/j.cels.2022.11.005

Funding

Howard Hughes Medical Institute (HHMI)
National Institutes of Health
1DP2CA250006-01
National Institutes of Health
1R01GM129011
National Institutes of Health
R01EB029483
National Institutes of Health
1R01EB026510
National Institutes of Health
R21EB030772
National Institutes of Health
R35GM143532
National Institutes of Health
R35GM143033
National Institutes of Health
R35GM138256
National Institutes of Health
4K00DK126120-03
National Institutes of Health
R01EB029483
National Institutes of Health
R35GM128947
National Institutes of Health
R01EB030946
National Institutes of Health
R01EB025256
National Institutes of Health
1UM1HG009402
National Institutes of Health
U54DK107965
National Institutes of Health
R21CA232244
National Institutes of Health
1RC2DK120535-01A1
National Institutes of Health
1U01 DK 127420-01
National Science Foundation
CBET-2034495
National Science Foundation
CBET-2145528
National Science Foundation
NSF Graduate Research Fellowship DGE-2141064
National Science Foundation
EF-1921677
National Science Foundation
UWSC10142 EF-2021552
Biotechnology and Biological Sciences Research Council
BB/S006206/1
Biotechnology and Biological Sciences Research Council
BB/M018040/1
Swiss National Science Foundation
Paul G. Allen Family Foundation
United States Air Force Office of Scientific Research
FA9550-22-1-0316
Wellcome Sanger Institute
LEAP 21-275
Parker Institute for Cancer Immunotherapy
Emory University
United States Department of Defense
Vannevar Bush Faculty Fellowship

Dates

Created
2023-03-01
Created from EPrint's datestamp field
Updated
2023-03-01
Created from EPrint's last_modified field

Caltech Custom Metadata

Caltech groups
Division of Biology and Biological Engineering (BBE)