Abstract
Fever is a universal response to infection, and opportunistic pathogens such as Candida albicans have evolved complex circuitry to sense and respond to heat. Here we harness RNA-seq and ChIP-seq to discover that the heat shock transcription factor, Hsf1, binds distinct motifs in nucleosome-depleted promoter regions to regulate heat shock genes and genes involved in virulence in C. albicans. Consequently, heat shock increases C. albicans host cell adhesion, damage and virulence. Hsf1 activation depends upon the molecular chaperone Hsp90 under basal and heat shock conditions, but the effects are opposite and in part controlled at the level of Hsf1 expression and DNA binding. Finally, we demonstrate that Hsp90 regulates global transcription programs by modulating nucleosome levels at promoters of stress-responsive genes. Thus, we describe a mechanism by which C. albicans responds to temperature via Hsf1 and Hsp90 to orchestrate gene expression and chromatin architecture, thereby enabling thermal adaptation and virulence.
Highlights
Fever is a universal response to infection, and opportunistic pathogens such as Candida albicans have evolved complex circuitry to sense and respond to heat
The majority of binding events were found at promoter regions close to transcription start sites (Supplementary Fig. 1a), with transcription of genes closest to Hsf1-binding sites being highly upregulated upon heat shock (Supplementary Fig. 1b)
The latter motif is a shorter version of the step-type non-canonical heat shock elements (HSE) identified in S. cerevisiae[32], while the former motif has not been reported for Hsf[1] in other organisms. It is the most predominant motif among the three, present at a higher frequency among Hsf1-bound peaks than the S. cerevisiae step-type non-canonical motif (Fig. 2b). These findings suggest that C. albicans and S. cerevisiae Hsf[1] have related yet distinct binding affinities, and that C. albicans Hsf[1] is capable of binding to nGAAn elements arranged in at least three configurations, presumably in different dimeric and trimeric forms
Summary
Fever is a universal response to infection, and opportunistic pathogens such as Candida albicans have evolved complex circuitry to sense and respond to heat. We demonstrate that Hsp[90] regulates global transcription programs by modulating nucleosome levels at promoters of stress-responsive genes. We describe a mechanism by which C. albicans responds to temperature via Hsf[1] and Hsp[90] to orchestrate gene expression and chromatin architecture, thereby enabling thermal adaptation and virulence. Cellular adaptation to thermal stress is modulated by complex functional relationships between Hsf[1] and the molecular chaperone Hsp[90], which influence signalling and gene expression. We use genome-scale approaches to explore how C. albicans responds to thermal insults, revealing that Hsf[1] and Hsp[90] govern nucleosome positioning, gene expression and virulence traits
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