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Systemic degradation of repressive transcription factors gates gene expression and cell fate specification

Predrag Jevtić1,2, Samuel R Witus1,2, Devlon M McCloud1,2

  • 1Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, USA.

Biorxiv : the Preprint Server for Biology
|June 29, 2026
PubMed

Insights

Proteasomes enable gene expression by degrading repressive transcription factors, releasing co-repressors from DNA. This process is vital for stem cell development and is disrupted by cancer mutations.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Epigenetics

Background:

  • Proteasomes primarily eliminate damaged proteins but also facilitate essential cellular functions.
  • The role of proteasomes in initiating gene expression is not well understood.
  • Repressive transcription factors and co-repressors play key roles in gene regulation.

Purpose of the Study:

  • To elucidate the mechanisms by which proteasomes regulate gene expression.
  • To identify the targets and regulatory pathways involving proteasomes in transcription.
  • To understand the role of proteasome-mediated degradation in cell fate specification.

Main Methods:

  • Investigated the interaction between proteasomes, E3 ligase SCFFBXL14, and TLE/Groucho co-repressors.
  • Utilized techniques to study the degradation of transcription factors and their impact on chromatin.
  • Analyzed cancer mutations in TLE1 to understand their functional consequences.

Main Results:

  • Proteasomes degrade repressive transcription factors, leading to the ejection of TLE/Groucho co-repressors from chromatin.
  • The E3 ligase SCFFBXL14 mediates this degradation, dependent on TLE presentation.
  • Continuous co-repressor turnover is essential for stem cell gene expression and is impaired by cancer-associated TLE1 mutations.

Conclusions:

  • Systemic degradation of repressive transcription factors by proteasomes is a key mechanism for regulating gene expression.
  • This process establishes co-repressor dynamics critical for cell fate specification.
  • Dysregulation of this pathway, observed in cancer, highlights its importance in normal cellular function.
Keywords:
cancergene repressionproteasomequality controlstem cell differentiationubiquitin

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