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Gene syntax defines supercoiling-mediated transcriptional feedback.

Christopher P Johnstone1, Kasey S Love2, Sneha R Kabaria1

  • 1Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

Science (New York, N.Y.)
|April 30, 2026
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Summary

Transcription-induced supercoiling regulates adjacent gene expression based on gene syntax. This finding improves the design of synthetic gene circuits by tuning expression, noise, and stoichiometry.

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Area of Science:

  • Molecular Biology
  • Systems Biology
  • Synthetic Biology

Background:

  • Gene syntax, the arrangement of genes and regulatory elements, influences gene circuit dynamics.
  • The molecular mechanisms by which transcription at one locus affects adjacent gene transcription are not fully understood.

Purpose of the Study:

  • To investigate the role of supercoiling-mediated feedback in regulating gene expression based on gene syntax.
  • To apply syntax as a design parameter for improving synthetic gene circuits.

Main Methods:

  • Utilized various assays to measure syntax- and induction-dependent chromatin structure formation in human induced pluripotent stem cells.
  • Developed and optimized compact gene circuits using gene syntax as a design parameter.

Main Results:

  • Demonstrated that supercoiling-mediated feedback arises from transcription and regulates adjacent gene expression in a syntax-specific manner.
  • Successfully tuned expression mean, noise, and stoichiometry of synthetic gene circuits across different delivery methods and cell types.

Conclusions:

  • Supercoiling-mediated feedback is a key mechanism regulating gene expression in response to gene arrangement.
  • Integrating supercoiling feedback into models enhances understanding of both natural and synthetic gene regulatory systems.
  • Gene syntax is a critical design parameter for engineering predictable and tunable gene circuits.