The sound of silence: Transgene silencing in mammalian cell engineering

Alan Cabrera, Hailey I. Edelstein, Fokion Glykofrydis, Kasey S. Love, Sebastian Palacios, Josh Tycko, Meng Zhang, Sarah Lensch, Cara E. Shields, Mark Livingston, Ron Weiss, Huimin Zhao, Karmella A. Haynes, Leonardo Morsut, Yvonne Y. Chen, Ahmad S. Khalil, Wilson W. Wong, James J. Collins, Susan J. Rosser, Karen PolizziMichael B. Elowitz, Martin Fussenegger, Isaac B. Hilton, Joshua N. Leonard, Lacramioara Bintu, Kate E. Galloway, Tara L. Deans

Research output: Contribution to journalReview articlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)950-973
Number of pages24
JournalCell Systems
Issue number12
StatePublished - Dec 21 2022


  • genome engineering
  • mammalian synthetic biology
  • synthetic gene circuit stability
  • transgene silencing

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Histology


Dive into the research topics of 'The sound of silence: Transgene silencing in mammalian cell engineering'. Together they form a unique fingerprint.

Cite this