Systematic functional profiling of transcription factor networks in Cryptococcus neoformans

Abstract

Cryptococcus neoformans causes life-threatening meningoencephalitis in humans, but its overall biological and pathogenic regulatory circuits remain elusive, particularly due to the presence of an evolutionarily divergent set of transcription factors (TFs). Here, we report the construction of a high-quality library of 322 signature-tagged gene-deletion strains for 155 putative TF genes previously predicted using the DNA-binding domain TF database, and examine their in vitro and in vivo phenotypic traits under 32 distinct growth conditions. At least one phenotypic trait is exhibited by 145 out of 155 TF mutants (93%) and ∼85% of them (132/155) are functionally characterized for the first time in this study. The genotypic and phenotypic data for each TF are available in the C. neoformans TF phenome database (http://tf.cryptococcus.org). In conclusion, our phenome-based functional analysis of the C. neoformans TF mutant library provides key insights into transcriptional networks of basidiomycetous fungi and human fungal pathogens.

Unraveling Fungal Radiation Resistance Regulatory Networks through the Genome-Wide Transcriptome and Genetic Analyses of Cryptococcus neoformans

“…Nevertheless, sophisticated homeostasis of ergosterol biosynthesis appears to be more critical for stress resistance than simple downregulation of ergosterol biosynthesis. Supporting this finding, this study and previous studies showed that deletion of SRE1 , which is a key positive regulator of ergosterol biosynthesis genes, increased susceptibility to oxidative stress (49) and gamma radiation. Furthermore, S. cerevisiae erg3 Δ and erg6 Δ mutants were also hypersensitive to hydrogen peroxide (60).…”

“…A similar phenomenon has been also reported in the C. neoformans UPR pathway, in which the evolutionarily conserved Ire1 kinase regulates the evolutionarily divergent TF Hxl1 (46). Therefore, it does not seem uncommon that an evolutionarily divergent fungal TF is controlled by a conserved upstream kinase, as suggested previously (49). …”

“…To support further that cellular ergosterol homeostasis was involved in gamma radiation resistance, we tested the gamma radiation resistance of strains with Sre1 or Hob1 deleted, which are 2 TFs affecting sterol biosynthesis in C. neoformans (49, 50). Both sre1 Δ and hob1 Δ mutants exhibited severe growth defects when exposed to gamma radiation (Fig.…”

“…A previous large-scale functional analysis of C. neoformans TFs uncovered several mutants exhibiting altered susceptibility to genotoxic stresses (49). However, most of them were involved in normal growth or played pleiotropic roles in diverse stress responses, in stark contrast to Bdr1, which plays genotoxic stress-specific roles.…”

A transcription factor, MrMsn2, in the dimorphic fungus Metarhizium rileyi is essential for dimorphism transition, aggravated pigmentation, conidiation and microsclerotia formation

“…DNA‐binding and multimerization domains are often used to classify transcriptional factors (TFs) into basic leucine zipper, zinc finger motif, helix–turn–helix and helix–loop–helix types (Park et al ., 2008; Chai et al ., 2012; Jung et al ., 2015; Yin et al ., 2017). As the core of signalling pathway, fungal TFs are important for transcriptional regulation of gene expression during cellular growth, secondary metabolism, stress responses and pathogenesis (Klug, 2010; Hong et al ., 2013; Liu et al ., 2013; Marinho et al ., 2014; Zhang et al ., 2014; Huang et al ., 2015; Shelest, 2017; Yin et al ., 2017; Song et al ., 2018).…”