Histone modification by lysine acetylation through writers (KATs) and erasers (KDACs).

<p>Much of the mechanistic knowledge about the role of chromatin modifications in gene expression regulation comes from the nonpathogenic baker’s yeast (for excellent recent reviews, see [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005938#ppat.1005938.ref065" target="_blank">65</a>–<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005938#ppat.1005938.ref067" target="_blank">67</a>]). Although the precise mechanisms of the interplay between writers, readers, and erasers remain ill-defined in many cases, it is fair to speculate that histone modifiers may play pivotal roles in the adaption of fungal pathogens to host immune defense. The major nucleosome building blocks, histones H2A, H2B, H3, and H4, are subject to dynamic and reversible posttranslational modifications (PTMs) by several KATs and KDACs functioning as writers and erasers of epigenetic marks. KATs like the Rtt109, which is a fungal-specific writer, and the cognate Hst3 eraser recognize the lysine residue K56 on histone H3. The KAT Esa1 acts primarily on H2A/H2B and H2AZ, with Hda1 and Hos3 acting as erasers (Panel A). By contrast, Hat1 targets mainly, though not exclusively, newly synthesized cytoplasmic histone H4 for the purpose of nuclear nucleosome remodeling during DNA damage repair [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005938#ppat.1005938.ref037" target="_blank">37</a>], as well as other processes demanding nucleosome exchange. The pleiotropic KAT Gcn5 acts mainly on histone H4 and H3. Each N-terminal histone lysine can be recognized by several redundant KATs/KDACs. Histone H3 and H4 are modified by several writers and erasers in <i>C</i>. <i>albicans</i>, creating extensive combinatorial complexity and many possibilities for gene regulation depending on the cellular context. For example, the KDACs, Rpd3/31, Hda1, and the SET3C complex consisting of Set3 and Hos2 [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005938#ppat.1005938.ref029" target="_blank">29</a>] act mainly on histone H3 and H4 (Panel B). Notably, kinases such as Cst20 (Panel A) and histone methyltransferases such as Dot1 and Set2 show restricted lysine specificities for histone H2B and H3, respectively. Panel C: A number of modulators of KATs/KDACs modulate (inhibit or activate) several KATs/KDACs, whereas others appear enzyme specific. Of note, no activator for KDACs have been identified for fungal KDACs, although several are known for mammalian KDACs [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005938#ppat.1005938.ref056" target="_blank">56</a>,<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005938#ppat.1005938.ref083" target="_blank">83</a>,<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005938#ppat.1005938.ref087" target="_blank">87</a>,<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005938#ppat.1005938.ref096" target="_blank">96</a>,<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005938#ppat.1005938.ref104" target="_blank">104</a>,<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005938#ppat.1005938.ref112" target="_blank">112</a>,<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005938#ppat.1005938.ref121" target="_blank">121</a>,<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005938#ppat.1005938.ref141" target="_blank">141</a>,<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005938#ppat.1005938.ref155" target="_blank">155</a>–<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005938#ppat.1005938.ref157" target="_blank">157</a>,<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005938#ppat.1005938.ref162" target="_blank">162</a>–<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005938#ppat.1005938.ref165" target="_blank">165</a>]. TSA, trichostatin A; SB, sodium butyrate; SAHA, suberoylanilide hydroxamic acid; VPA, valporic acid; NAM, nicotinamide; CPTH2, Cyclopentylidene-[4-(4-chlorophenyl)thiazol-2-yl)hydrazine; CPTH6, 3-methylcyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl]hydrazine; NU9056, 5-(1,2-Thiazol-5-yldisulfanyl)-1,2-thiazole; MG149, 2-(4-Heptylphenethyl)-6-hydroxybenzoic acid; CTPB, N-[4-Chloro-3-(trifluoromethyl)phenyl]-2-ethoxy-6-pentadecylbenzamide; TTK21, N-(4-Chloro-3-trifluoromethyl-phenyl)-2-n-propoxy- benzamide; HDPHs, histone dephoshorlyases; HMTs, histone methyltransferases; KATs, lysine acetyltransferases; KDACs, lysine deacetylases. Red boxes, fungal-specific modifications; grey circles, evolutionary conserved lysines in histone tails; orange ellipses, writer KATs; yellow ellipses, eraser KDACs; blue ellipses, histone dephosphorylases; cyan ellipses, histone kinases; green ellipses, histone methyltransferases.</p

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

Adaptation to changing environments and immune evasion is pivotal for fitness of pathogens. Yet, the underlying mechanisms remain largely unknown. Adaptation is governed by dynamic transcriptional re-programming, which is tightly connected to chromatin architecture. Here, we report a pivotal role for the HIR histone chaperone complex in modulating virulence of the human fungal pathogen Candida albicans. Genetic ablation of HIR function alters chromatin accessibility linked to aberrant transcriptional responses to protein as nitrogen source. This accelerates metabolic adaptation and increases the release of extracellular proteases, which enables scavenging of alternative nitrogen sources. Furthermore, HIR controls fungal virulence, as HIR1 deletion leads to differential recognition by immune cells and hypervirulence in a mouse model of systemic infection. This work provides mechanistic insights into chromatin-coupled regulatory mechanisms that fine-tune pathogen gene expression and virulence. Furthermore, the data point toward the requirement of refined screening approaches to exploit chromatin modifications as antifungal strategies