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Genome-wide Analysis of Histone Modifications Distribution using the Chromatin Immunoprecipitation Sequencing Method in Magnaporthe oryzae
Published on: June 2, 2021
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.
Abstract:
Adaptive responses to environmental stimuli are integral to the survival and virulence of microbial pathogens. The thermally dimorphic human fungal pathogen Histoplasma senses temperature to transition between a mold form in soil and a pathogenic yeast in mammalian hosts. The contributions of chromatin-modifying enzymes to the ability of Histoplasma to appropriately respond to temperature have never been explored. Through chemical inhibition and genetics, we determined that the class I histone deacetylase (HDAC) RPD3 is required for normal Histoplasma yeast morphology at 37 °C. Rpd3 regulated the expression of key morphology-specific genes, including critical virulence factors and transcription factors (TFs), was required for normal DNA-binding activity of yeast-promoting TFs, and influenced histone acetylation levels at the loci of putative pro-filamentation TFs. Furthermore, Rpd3 was required for virulence in a macrophage model of infection. Taken together, Rpd3 is a critical regulatory component that both activates the pathogenesis program and represses the filamentation program to enable thermal dimorphism in Histoplasma. This work uncovers the crucial role that chromatin regulation plays in temperature response of this ubiquitous pathogen.
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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