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Related Concept Videos

RNA Polymerase II Accessory Proteins02:36

RNA Polymerase II Accessory Proteins

Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
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Efficient Transcriptionally Controlled Plasmid Expression System for Investigation of the Stability of mRNA Transcripts in Primary Alveolar Epithelial Cells
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Ratiometric transcriptional activation by protein degradation.

Melissa A Gray1, Katelyn L Randal1, Jennifer A Co1

  • 1Department of Chemistry, Stanford University, Stanford, CA, 94305, USA.

Biorxiv : the Preprint Server for Biology
|June 4, 2026
PubMed
Summary

Scientists developed a new method, ratiometric transcriptional activation, to program gene expression based on protein levels. This synthetic biology tool enables sensitive detection of protein degradation for various applications.

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Area of Science:

  • Synthetic biology
  • Molecular biology
  • Genetics

Background:

  • Cells naturally regulate gene expression in response to protein abundance changes.
  • Synthetic circuits that mimic native post-transcriptional regulation are needed for programmable gene expression.
  • Converting protein degradation into transcriptional outputs offers a powerful synthetic biology approach.

Purpose of the Study:

  • To discover and describe design principles for converting protein degradation into transcriptional outputs in live cells.
  • To develop a sensitive and scalable method for detecting protein abundance changes.
  • To enable applications in areas like cancer research and drug discovery.

Main Methods:

  • Development of ratiometric transcriptional activation circuits.
  • Utilizing a transcriptional inhibitor-protein of interest fusion and a transcription factor.
  • Implementation in single cells using triply orthogonal circuits and in multicellular pools.
  • Employing outputs such as cell survival, fluorescent protein expression, or barcode sequencing.

Main Results:

  • Demonstrated effective conversion of protein degradation into transcriptional outputs.
  • Achieved high sensitivity in detecting protein abundance changes at scale.
  • Showcased the ability to operate independently of the protein downregulation mechanism.
  • Enabled simultaneous detection of multiple protein downregulation events.
  • Successfully applied circuits to oncogenic targets.

Conclusions:

  • Ratiometric transcriptional activation is a versatile synthetic biology tool for monitoring protein degradation.
  • This approach allows for sensitive, scalable, and multiplexed detection of protein downregulation.
  • The technology has potential applications in discovering novel therapeutic agents, such as molecular glue degraders.