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Targets of the Sex Inducer homeodomain proteins are required for fungal development and virulence in Cryptococcus neoformans.

ABSTRACT: In the yeast Saccharomyces cerevisiae, the regulation of cell types by homeodomain transcription factors is a key paradigm; however, many questions remain regarding this class of developmental regulators in other fungi. In the human fungal pathogen Cryptococcus neoformans, the homeodomain transcription factors Sxi1? and Sxi2a are required for sexual development that produces infectious spores, but the molecular mechanisms by which they drive this process are unknown. To better understand homeodomain control of fungal development, we determined the targets of the Sxi2a-Sxi1? heterodimer using whole genome expression analyses paired with in silico and in vitro binding site identification methods. We identified Sxi-regulated genes that contained a site bound directly by the Sxi proteins that is required for full regulation in vivo. Among the targets of the Sxi2a-Sxi1? complex were many genes known to be involved in sexual reproduction, as well as several well-studied virulence genes. Our findings suggest that genes involved in sexual development are also important in mammalian disease. Our work advances the understanding of how homeodomain transcription factors control complex developmental events and suggests an intimate link between fungal development and virulence.

SUBMITTER: Mead ME

PROVIDER: S-EPMC4339537 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Targets of the Sex Inducer homeodomain proteins are required for fungal development and virulence in Cryptococcus neoformans.

Mead Matthew E ME Stanton Brynne C BC Kruzel Emilia K EK Hull Christina M CM

Molecular microbiology 20150116 5

In the yeast Saccharomyces cerevisiae, the regulation of cell types by homeodomain transcription factors is a key paradigm; however, many questions remain regarding this class of developmental regulators in other fungi. In the human fungal pathogen Cryptococcus neoformans, the homeodomain transcription factors Sxi1α and Sxi2a are required for sexual development that produces infectious spores, but the molecular mechanisms by which they drive this process are unknown. To better understand homeodo ...[more]

PMID: 25476490

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Project description:To identify genes regulated by the homeodomain transcription factors Sxi1M-NM-1 and Sxi2a (Sex Inducer 1M-NM-1 and 2a) in Cryptococcus neoformans, we carried out a whole-genome expression experiment. We performed two independent whole-genome microarray experiments comparing transcript levels in cells that either possessed or were lacking the Sxi proteins. In the first experiment we compared the expression profile of a haploid sxi1M-NM-1M-NM-^T strain to that of a haploid strain expressing both SXI1M-NM-1 and an inducible copy of SXI2a (Sxi +). In the second experiment, we compared the expression profile of a wild type cross (JEC20 x JEC21) to the expression profile of a cross whose mating partners did not possess either of the transcription factors (sxi2aM-bM-^HM-^F x sxi1M-NM-1M-bM-^HM-^F)(Sxi -). In both experiments RNA from each condition was harvested, labeled, and hybridized competitively to a spotted oligonucleotide microarray representing the approximately 6,500 genes in the C. neoformans genome. The resulting data was analyzed in Limma using standard methods. In the Sxi (+) experiment, each strain (M-NM-^Tsxi1M-NM-1 and the Sxi-Inducible strain) were grown overnight in liquid YPD, diluted back to an OD600 of 0.2, grown to log phase, and then switched to growth in liquid YPGal media for 6 hrs. The M-NM-^Tsxi1M-NM-1 strain was designated the control condition. Two biological replicates were used and in the first replicate there were two technical replicates for each dye orientation (4 replicates total). For the second Sxi (+) biological replicate, there were three total technical replicates, and one of those was a dye swap. For Sxi deletion crosses, strains (JEC20 x JEC21 or M-NM-^Tsxi1M-NM-1 x M-NM-^Tsxi2a) were mixed and plated onto V8 media (pH 7.0) and incubated at 22M-BM-0C in the dark for approximately 16 hours. The wild type (JEC20 x JEC21) cross was designated as the control in this experiment. Eight total hybridizations were carried out that consisted of 2 biological replicates and four technical replicates for each biological replicate (2 technical replicates per dye swap).

Dataset Information

Targets of the Sex Inducer homeodomain proteins are required for fungal development and virulence in Cryptococcus neoformans.

Publications

Targets of the Sex Inducer homeodomain proteins are required for fungal development and virulence in Cryptococcus neoformans.

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