Local and regional chromatin silencing inCandida glabrata: consequences for adhesion and the response to stress

Abstract

Candida glabrata is a fungal pathogen frequently found as a commensal in humans. To colonize and disseminate successfully in the mammalian host, C. glabrata must detect signals within the host and reprogram gene expression to respond appropriately to hostile environmental conditions. One of the layers of regulation of expression of many virulence-related genes (adhesin-encoding genes, genes involved in response to oxidative stress and xenobiotics) is achieved through epigenetic mechanisms. Local and regional silencing is mediated by the activity of two NAD(+)-dependent histone deacetylases, Hst1 and Sir2, respectively, repressing many virulence genes. Hst1 and Sir2 interact with different repressor complexes to achieve regional or local silencing. Sir2 can associate with Sir4, which is then recruited to the telomere by Rap1 and yKu. Deacetylation of the histone tails creates high affinity binding sites for new molecules of the Sir complex, thereby spreading the silent domain over >20 kb. Many of the adhesin-encoding EPA genes are subject to this regulation. Hst1 in turn associates with the Sum1-Rfm1 complex. Sum1 is a DNA-binding protein, which recognizes specific sites at individual promoters, recruiting Hst1 to specific genes involved in the response to oxidative stress and xenobiotics, which results in their repression.

Evolution of reduced co-activator dependence led to target expansion of a starvation response pathway

“…Among the remaining genes, a significant number (25 genes) are predicted to be involved in responses to non-phosphate related stresses, including osmotic (seven genes) and oxidative (seven genes) stresses. In addition to roles in other stress responses, a smaller group of CgPho4 targets (9 and 3 genes) have potential functions in cell wall synthesis and cell adhesion, two traits that were known to be relevant for survival and virulence in the host (Atanasova et al, 2013; De Las Peñas et al, 2015; Luo and Samaranayake, 2002; Jawhara et al, 2012; Fabre et al, 2014). A similar observation has been made before in C. glabrata , where limitation of nicotinic acid was sufficient to induce genes mediating a cellular adhesion phenotype (Domergue et al, 2005).…”

The role of genomic location and flanking 3′UTR in the generation of functional levels of variant surface glycoprotein in Trypanosoma brucei

“…In addition, the invariably telomeric location of the active VSG would facilitate the DNA rearrangements mediating VSG switching. DNA recombination reactions at telomeres mediate the generation of sequence diversity within polymorphic gene families involved in phenotypic or antigenic variation which are frequently telomeric (Keely et al ., ; Scherf et al ., ; de Las Penas et al ., ; Lue and Yu, ). In T. brucei this is also the case, and the telomeric VSG can be switched either through telomere exchange or through gene conversions (Li, ; McCulloch et al ., ).…”

Choose Your Own Adventure: The Role of Histone Modifications in Yeast Cell Fate

“…This gene family is similar to the ALS and EPA adhesin gene families in the human pathogens Candida albicans and Candida glibrata , respectively. In particular, the EPA genes of C. glibrata are also adjacent to telomeres and subject to metastable gene silencing, with activation of individual EPA genes occurring in different host environments and generating cell surface variation for the pathogen [75]. Understanding the regulatory mechanisms controlling expression of these gene families is therefore of high clinical relevance due to their role in promoting adherence to host cells, such as human epithelial cells, and biofilm formation on abiotic surfaces, including implanted medical devices [76].…”