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In vivo Application of the REMOTE-control System for the Manipulation of Endogenous Gene Expression

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Programmable promoter editing for precise control of transgene expression.

Sneha R Kabaria¹, Yunbeen Bae¹, Mary E Ehmann¹

¹Department of Chemical Engineering, MIT, Cambridge, MA, USA.

Nature Biotechnology

|October 14, 2025

Summary

Scientists created a new gene editing tool, DIAL, for precise control over transgene expression. This framework allows for heritable, tunable gene expression levels, advancing synthetic biology and cell fate engineering.

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Area of Science:

Synthetic Biology
Molecular Biology
Gene Regulation

Background:

Precise control over gene expression is crucial for understanding cellular functions and engineering biological systems.
Existing methods for titrating transgene expression often lack fine-scale control, heritability, or modularity.

Purpose of the Study:

To develop a novel, modular, and extensible framework (DIAL) for creating editable promoters that enable fine-scale, heritable control of transgene expression.
To demonstrate the ability of the DIAL system to generate tunable expression setpoints and respond to external stimuli.

Main Methods:

Development of the DIAL framework utilizing recombinase-mediated excision of DNA spacers within a promoter region.
Engineering synthetic zinc finger transcription factor binding sites and core promoters.
Integration of small-molecule inducible systems for temporal control of transcription factors and recombinases.
Lentiviral delivery of the DIAL system into primary cells and induced pluripotent stem cells.

Main Results:

The DIAL framework successfully generated a tunable range of unimodal transgene expression setpoints from a single editable promoter.
The system demonstrated heritable transgene expression levels after promoter editing.
DIAL enabled temporally defined, user-guided control of gene expression in various cell types.
Application of DIAL facilitated mapping of transgene levels to cell fate determination during induced motor neuron conversion.

Conclusions:

The DIAL framework provides a powerful tool for precisely tailoring transgene expression with heritable and tunable control.
This system enhances the predictability and performance of gene circuits for diverse applications in synthetic biology and regenerative medicine.
DIAL offers new opportunities for engineering cellular states and studying gene function through controlled expression levels.