The Candida albicans HIR histone chaperone regulates the yeast-to-hyphae transition by controlling the sensitivity to morphogenesis signals

Abstract

Morphological plasticity such as the yeast-to-hyphae transition is a key virulence factor of the human fungal pathogen Candida albicans. Hyphal formation is controlled by a multilayer regulatory network composed of environmental sensing, signaling, transcriptional modulators as well as chromatin modifications. Here, we demonstrate a novel role for the replication-independent HIR histone chaperone complex in fungal morphogenesis. HIR operates as a crucial modulator of hyphal development, since genetic ablation of the HIR complex subunit Hir1 decreases sensitivity to morphogenetic stimuli. Strikingly, HIR1-deficient cells display altered transcriptional amplitudes upon hyphal initiation, suggesting that Hir1 affects transcription by establishing transcriptional thresholds required for driving morphogenetic cell-fate decisions. Furthermore, ectopic expression of the transcription factor Ume6, which facilitates hyphal maintenance, rescues filamentation defects of hir1Δ/Δ cells, suggesting that Hir1 impacts the early phase of hyphal initiation. Hence, chromatin chaperone-mediated fine-tuning of transcription is crucial for driving morphogenetic conversions in the fungal pathogen C. albicans.

Epigenetic cell fate in Candida albicans is controlled by transcription factor condensates acting at super-enhancer-like elements

“…The TRNs regulating cell identity also involve unusually large regulatory regions in both fungi and mammals. The median size of mammalian ‘super-enhancers’ is >8 kb versus ~700 bp for typical enhancers 11 , and the regulatory regions of master white-opaque TFs are similarly expanded; the upstream intergenic regions of 6 of the 8 TFs are >7 kb, considerably larger than the average intergenic length of 557 bp in C. albicans 40 . White-opaque TFs bind overlapping regions upstream of the genes encoding the master TFs.…”

Candida albicans FRE8 encodes a member of the NADPH oxidase family that produces a burst of ROS during fungal morphogenesis

“…SOD5 has previously been shown to fall under control of Efg1 [ 13 ]. SOD5 and FRE8 were not identified by ChIP as direct targets of Efg1 or Cph1 [ 43 ] [ 44 ]; both are subject to chromatin remodeling control by Hir1 that works in concert with Efg1 to control genes for morphogenesis [ 45 ].…”

The histone chaperone HIR maintains chromatin states to control nitrogen assimilation and fungal virulence

“…We recently demonstrated that hir1 Δ/Δ C. albicans cells have impaired hyphal formation ( Jenull et al, 2017 ). In follow-up experiments, we also analyzed colony morphology in response to fetal calf serum (FCS) on synthetic complete (SC) medium.…”

“…HIR acts as transcriptional co-regulator affecting developmental processes in human, animal, or plant cells ( Amin et al, 2013 ; Banaszynski et al, 2013 ; Duc et al, 2015 ; Sadasivam and Huang, 2016 ; Tagami et al, 2004 ) but also regulates gene expression in unicellular yeasts, including S. cerevisiae ( Fillingham et al, 2009 ; Spector et al, 1997 ). As in S. cerevisiae ( Prochasson et al, 2005 ), the C. albicans HIR complex consists of the Hir1, Hir2, Hir3, and Hpc2 subunits ( Jenull et al, 2017 ; Stevenson and Liu, 2013 ). Besides transcriptional repression of histone genes ( Stevenson and Liu, 2013 ), HIR affects sensitivity to antifungal azoles ( Tscherner et al, 2015 ) and hyphal initiation in C. albicans ( Jenull et al, 2017 ).…”

“…As in S. cerevisiae ( Prochasson et al, 2005 ), the C. albicans HIR complex consists of the Hir1, Hir2, Hir3, and Hpc2 subunits ( Jenull et al, 2017 ; Stevenson and Liu, 2013 ). Besides transcriptional repression of histone genes ( Stevenson and Liu, 2013 ), HIR affects sensitivity to antifungal azoles ( Tscherner et al, 2015 ) and hyphal initiation in C. albicans ( Jenull et al, 2017 ). Given the crucial role of chromatin regulators in gene-expression control, it is not surprising that an imbalance of histones or a lack of various chromatin modifiers alter fungal morphogenesis and virulence ( Lee et al, 2015 ; Lopes da Rosa et al, 2010 ; Tscherner et al, 2015 ; Wurtele et al, 2010 ; Zacchi et al, 2010 ).…”