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Updated: Jun 7, 2025

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Combinatorial effector targeting (COMET) for transcriptional modulation and locus-specific biochemistry.

Caroline M Wilson1,2,3,4, Greg C Pommier2,3,5, Daniel D Richman6

  • 1Tetrad Graduate Program, University of California, San Francisco, CA 94158, USA.

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Summary

We developed COMET, a high-throughput screening platform, to discover novel transcriptional modulators by testing over 110,000 combinations of dCas9-based fusion proteins. This tool identifies gene expression regulators and novel protein interactions.

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Area of Science:

  • Genomics
  • Molecular Biology
  • Biochemistry

Background:

  • Coordinated regulation of human gene expression by protein functional units is a key biological challenge.
  • Identifying novel transcriptional modulators and understanding protein-domain interactions are crucial for functional genomics.

Purpose of the Study:

  • To introduce COMET, a high-throughput screening platform for combinatorial effector targeting.
  • To systematically investigate the influence of over 110,000 dCas9-based fusion protein combinations on transcription at endogenous human loci.
  • To identify novel transcriptional modulators and uncover new domain interactions.

Main Methods:

  • Generation of combinatorial dCas9-based fusion protein libraries with two to six effector domains.
  • High-throughput screening of over 110,000 protein combinations at endogenous human loci.
  • Analysis of cell type-specific transcriptional modulation and epistatic relationships.

Main Results:

  • Identification of over 5800 significant hits that modulate transcription.
  • Demonstration of cell type-specific transcriptional modulation.
  • Validation of synergistic and buffering effects of unexpected effector combinations.

Conclusions:

  • COMET is an effective method for discovering transcriptional effectors.
  • COMET serves as a functional genomics tool for identifying novel domain interactions.
  • COMET can direct locus-specific biochemistry for gene expression regulation.