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Updated: Jun 4, 2025

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Correlating disordered activation domain ensembles with gene expression levels.

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|January 4, 2025
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The structural flexibility of transcription factor activation domains (ADs) influences gene expression. Expanding the ensemble of HIF-1α ADs boosted activity, while CITED2 ADs showed no such link, suggesting plasticity is key for some ADs.

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Area of Science:

  • Molecular Biology
  • Biochemistry
  • Genetics

Background:

  • Transcription factors regulate gene expression by binding DNA.
  • Intrinsically disordered activation domains (ADs) lack fixed structures and exist as conformational ensembles.
  • Disordered protein regions often have sequence-encoded structural preferences linked to function.

Purpose of the Study:

  • To investigate the link between the structural preferences of AD ensembles and their transcriptional activity.
  • To determine if AD ensemble dimensions correlate with their ability to induce gene expression.

Main Methods:

  • Measured ensemble dimensions of two ADs (HIF-1α and CITED2) in live cells using fluorescence resonance energy transfer (FRET) microscopy.
  • Correlated structural ensemble data with transcriptional activity measurements.

Main Results:

  • Mutations expanding the HIF-1α AD ensemble increased transcriptional activity.
  • Mutations compacting the HIF-1α AD ensemble reduced transcriptional activity.
  • No correlation was found between ensemble dimensions and activity for CITED2 AD.

Conclusions:

  • AD structural plasticity is critical for regulating HIF-1α function.
  • A link between AD ensemble dimensions and transcriptional activity may exist for some proteins.
  • Findings have implications for understanding transcriptional regulation and dysfunction.