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Transcrptional profiles of Cryptococcous neoformans Gsb1 at non-stress and oxidative stress conditions

ABSTRACT: Purpose: To identify the downstream genes whose expression levels are affected by the deletion of gsb1 under non-stress and oxidative stress conditions, we compared the RNA-seq based transcriptional profiles of wild-type and gsb1 cells. Methods: mRNA profiles of cells grown at non-stress and oxidative stress conditions were generated by RNA-seq using Illumina GAIIx. The sequence reads that passed quality filters were mapped to reference genome and the normalized RPKM values were calculated by CLC Genomics Workbench. Results: RNA-Seq analysis during normal growth revealed increased expression of a number of genes involved in mitochondrial respiration and cell cycle, but decreased expression of several genes involved in the mating-responsive MAPK signaling pathway. Moreover, RNA-Seq analysis under oxidative stress revealed that several genes involved in ROS defense, cell wall remodeling, and protein glycosylation were highly induced in the wild-type strain but not in gsb1. Conclusions: This study proposed that Gsb1 is a key transcriptional regulator modulating growth, anti-stress responses, differentiation, and virulence in C. neoformans.

ORGANISM(S): Cryptococcus neoformans H99

PROVIDER: GSE96543 | GEO | 2017/08/17

SECONDARY ACCESSION(S): PRJNA378989

REPOSITORIES: GEO

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Project description:Cryptococcus neoformans is an important pathogen that annually kills 200,000 people worldwide. It survives in the environment as a yeast or spore and can also proliferate within host macrophages after being inhaled into the lungs. In conditions of immunocompromise, cryptococcal cells can escape from the lungs to the brain, where they cause a deadly meningoencephalitis that is both difficult and expensive to treat. Cryptococcal adaptation to the harsh lung environment is a critical first step in its pathogenesis, and consequently a compelling topic of study. This adaptation is mediated by a complex transcriptional program that integrates cellular responses to environmental stimuli. Although several key regulators in this process have been examined, one important protein complex that modulates transcription yet remains understudied in C. neoformans is the Mediator complex. In other organisms, this complex promotes transcription of specific genes by increasing the assembly of the RNA Polymerase II pre-initiation complex. We have focused on the Kinase Module of the Mediator complex, which consists of cyclin C (Ssn801), cyclin-dependent kinase 8 (Cdk8), and two other proteins (Med12 and Med13). This module provides important inhibitory control of Mediator complex assembly and activity. Using a transcriptomics approach, we discovered that Cdk8 and Ssn801 together regulate cryptococcal functions relevant to pathogenesis, including the response to oxidative stress. Deletion of CDK8 resulted in altered mitochondrial morphology and the dysregulation of genes involved in oxidation-reduction processes, such that this strain exhibited increased susceptibility to oxidative stress. This resulted in an inability of mutant cells to proliferate within phagocytes, decreased lung burdens, and attenuated virulence in in vivo studies. These findings increase our understanding of cryptococcal adaptation to the host environment and its regulation of oxidative stress resistance and virulence.

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Transcrptional profiles of Cryptococcous neoformans Gsb1 at non-stress and oxidative stress conditions

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