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The sound of silence: Transgene silencing in mammalian cell engineering

Cabrera, Alan and Edelstein, Hailey I. and Glykofrydis, Fokion and Love, Kasey S. and Palacios, Sebastian and Tycko, Josh and Zhang, Meng and Lensch, Sarah and Shields, Cara E. and Livingston, Mark and Weiss, Ron and Zhao, Huimin and Haynes, Karmella A. and Morsut, Leonardo and Chen, Yvonne Y. and Khalil, Ahmad S. and Wong, Wilson W. and Collins, James J. and Rosser, Susan J. and Polizzi, Karen and Elowitz, Michael B. and Fussenegger, Martin and Hilton, Isaac B. and Leonard, Joshua N. and Bintu, Lacramioara and Galloway, Kate E. and Deans, Tara L. (2022) The sound of silence: Transgene silencing in mammalian cell engineering. Cell Systems, 13 (12). pp. 950-973. ISSN 2405-4712. PMCID PMC9880859. doi:10.1016/j.cels.2022.11.005.

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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.

Item Type:Article
Related URLs:
URLURL TypeDescription
Cabrera, Alan0000-0002-2546-0260
Edelstein, Hailey I.0000-0002-8077-5492
Glykofrydis, Fokion0000-0002-0865-4573
Love, Kasey S.0000-0001-7544-0340
Tycko, Josh0000-0002-4108-0575
Zhang, Meng0000-0002-4076-6276
Lensch, Sarah0000-0003-1450-3242
Shields, Cara E.0000-0002-3791-8259
Haynes, Karmella A.0000-0002-5975-577X
Morsut, Leonardo0000-0001-7049-3478
Chen, Yvonne Y.0000-0002-5583-119X
Khalil, Ahmad S.0000-0002-8214-0546
Wong, Wilson W.0000-0001-8394-889X
Rosser, Susan J.0000-0002-2560-6485
Polizzi, Karen0000-0001-5435-2667
Elowitz, Michael B.0000-0002-1221-0967
Fussenegger, Martin0000-0001-8545-667X
Hilton, Isaac B.0000-0002-3064-8532
Leonard, Joshua N.0000-0003-4359-6126
Bintu, Lacramioara0000-0001-5443-6633
Galloway, Kate E.0000-0001-7416-3193
Deans, Tara L.0000-0002-2361-2195
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.
Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:12
PubMed Central ID:PMC9880859
Record Number:CaltechAUTHORS:20230203-893712500.43
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:119035
Deposited By: Research Services Depository
Deposited On:01 Mar 2023 01:52
Last Modified:01 Mar 2023 01:52

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