Abstract
Eukaryotic cells integrate layers of gene regulation to coordinate complex cellular processes; however, mechanisms of post-transcriptional gene regulation remain poorly studied. The human fungal pathogen Histoplasma capsulatum (Hc) responds to environmental or host temperature by initiating unique transcriptional programs to specify multicellular (hyphae) or unicellular (yeast) developmental states that function in infectivity or pathogenesis, respectively. Here we used recent advances in next-generation sequencing to uncover a novel re-programming of transcript length between Hc developmental cell types. We found that ~2% percent of Hc transcripts exhibit 5’ leader sequences that differ markedly in length between morphogenetic states. Ribosome density and mRNA abundance measurements of differential leader transcripts revealed nuanced transcriptional and translational regulation. One such class of regulated longer leader transcripts exhibited tight transcriptional and translational repression. Further examination of these dually repressed genes revealed that some control Hc morphology and that their strict regulation is necessary for the pathogen to make appropriate developmental decisions in response to temperature.
Highlights
Environmental human pathogens have evolved the ability to survive in human hosts as well as diverse environmental reservoirs
We found that a fraction of Histoplasma capsulatum (Hc) transcripts have differential transcript architecture in hyphae and yeast, exhibiting 5’ leader sequences that differ markedly
Total RNA was isolated from biological duplicates of yeast or hyphal cultures and strand specific cDNA libraries were created from poly(A)enriched RNA and sequenced using paired-end deep-sequencing
Summary
Environmental human pathogens have evolved the ability to survive in human hosts as well as diverse environmental reservoirs. A hallmark of environmental pathogens is their capacity to adapt to varied growth conditions such as differences in temperature, alterations in nutrient sources, as well as exposure to the host immune system. The dimorphic human fungal pathogen, Histoplasma capsulatum (Hc), is one such environmental pathogen that responds to an increase in temperature inside a mammalian host by dramatically altering its cellular morphology and gene expression programs to cause disease. The temperature-regulated differentiation of Hc between the hyphal and yeast forms can be recapitulated in the laboratory by switching the temperature from room temperature (RT) to 37°C, making Hc a unique organism for studying the regulation of gene expression during multicellular development, environmental signal transduction, and adaptation of a pathogen to a mammalian host
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