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Chromatin-mediated regulation of nucleolar structure and RNA Pol I localization by TOR

Chi Kwan Tsang1, Paula G Bertram, Wandong Ai

  • 1Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.

The EMBO Journal
|November 12, 2003
PubMed

Insights

Target of rapamycin (TOR) inhibits nucleolar size and ribosomal DNA transcription. TOR regulates histone deacetylase association with chromatin, impacting cell growth and proliferation via a chromatin-mediated mechanism.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Epigenetics

Background:

  • The target of rapamycin (TOR) pathway is crucial for regulating cell growth and proliferation.
  • TOR's precise role in ribosome biogenesis and nucleolar structure remains incompletely understood.
  • Nutrient availability significantly influences cellular processes through pathways like TOR.

Purpose of the Study:

  • To elucidate the mechanism by which TOR signaling influences nucleolar size and function.
  • To investigate the role of chromatin modifications in TOR-mediated regulation of ribosome biogenesis.
  • To understand how TOR inhibition affects RNA polymerase I (Pol I) localization and ribosomal DNA (rDNA) transcription.

Main Methods:

  • Comparative analysis of nucleolar size in yeast and mammalian cells under TOR inhibition.
  • Assessment of RNA polymerase I (Pol I) localization and rDNA transcription rates.
  • Investigation of histone deacetylase (HDAC) association with rDNA chromatin.
  • Analysis of histone H4 acetylation patterns and their impact on nucleolar morphology and Pol I activity.

Main Results:

  • TOR inhibition (via rapamycin or nutrient starvation) significantly reduces nucleolar size in both yeast and mammalian cells.
  • In yeast, TOR inhibition leads to RNA polymerase I (Pol I) release from the nucleolus and decreased rDNA transcription.
  • TOR signaling modulates the association of Rpd3-Sin3 histone deacetylase (HDAC) with rDNA, causing histone H4 deacetylation.
  • Mutations affecting histone H4 acetylation or Rpd3 deacetylase activity mimic or block TOR-dependent nucleolar changes.

Conclusions:

  • TOR regulates nucleolar structure and rRNA gene expression through a chromatin-mediated mechanism involving histone deacetylation.
  • Histone H4 deacetylation is a key event linking TOR inhibition to reduced nucleolar size and Pol I activity.
  • This mechanism allows cells to adjust ribosome biogenesis in response to nutrient availability.

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