The Rpd3 histone deacetylase is a critical regulator of temperature-mediated morphogenesis and virulence in the human

Nebat Ali1, Mark Voorhies1, Rosa A Rodriguez1

  • 1Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, United States of America.

Plos Biology
|March 17, 2026
PubMed

Insights

Histoplasma fungal pathogens use temperature sensing for survival. The histone deacetylase RPD3 enzyme is essential for Histoplasma yeast form, regulating virulence and thermal dimorphism.

Area of Science:

  • Microbiology
  • Mycology
  • Molecular Biology

Background:

  • Microbial pathogens adapt to environmental cues for survival and virulence.
  • The thermally dimorphic fungus Histoplasma transitions between mold and yeast forms based on temperature.
  • Chromatin-modifying enzymes' roles in Histoplasma's temperature response were previously unexplored.

Purpose of the Study:

  • To investigate the role of chromatin-modifying enzymes, specifically histone deacetylases (HDACs), in Histoplasma's thermal dimorphism.
  • To determine if HDACs influence Histoplasma's morphology, gene expression, and virulence in response to temperature.

Main Methods:

  • Chemical inhibition of class I histone deacetylase (HDAC) RPD3.
  • Genetic manipulation of RPD3 in Histoplasma.
  • Analysis of gene expression, transcription factor DNA-binding activity, and histone acetylation.
  • Assessment of virulence in a macrophage model of infection.

Main Results:

  • Class I HDAC RPD3 is essential for normal Histoplasma yeast morphology at 37 °C.
  • RPD3 regulates key morphology-specific genes, including virulence factors and transcription factors.
  • RPD3 influences transcription factor DNA-binding activity and histone acetylation patterns.
  • RPD3 is required for Histoplasma virulence in a macrophage infection model.

Conclusions:

  • RPD3 is a critical regulator of thermal dimorphism in Histoplasma.
  • RPD3 activates the pathogenic yeast program and represses the mold (filamentation) program.
  • Chromatin regulation by RPD3 is crucial for Histoplasma's temperature response and pathogenesis.

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