Chromatin Profiling of the Repetitive and Nonrepetitive Genomes of the Human Fungal Pathogen Candida albicans

Abstract

Eukaryotic genomes are packaged into chromatin structures that play pivotal roles in regulating all DNA-associated processes. Histone posttranslational modifications modulate chromatin structure and function, leading to rapid regulation of gene expression and genome stability, key steps in environmental adaptation. Candida albicans, a prevalent fungal pathogen in humans, can rapidly adapt and thrive in diverse host niches. The contribution of chromatin to C. albicans biology is largely unexplored. Here, we generated the first comprehensive chromatin profile of histone modifications (histone H3 trimethylated on lysine 4 [H3K4me3], histone H3 acetylated on lysine 9 [H3K9Ac], acetylated lysine 16 on histone H4 [H4K16Ac], and γH2A) across the C. albicans genome and investigated its relationship to gene expression by harnessing genome-wide sequencing approaches. We demonstrated that gene-rich nonrepetitive regions are packaged into canonical euchromatin in association with histone modifications that mirror their transcriptional activity. In contrast, repetitive regions are assembled into distinct chromatin states; subtelomeric regions and the ribosomal DNA (rDNA) locus are assembled into heterochromatin, while major repeat sequences and transposons are packaged in chromatin that bears features of euchromatin and heterochromatin. Genome-wide mapping of γH2A, a marker of genome instability, identified potential recombination-prone genomic loci. Finally, we present the first quantitative chromatin profiling in C. albicans to delineate the role of the chromatin modifiers Sir2 and Set1 in controlling chromatin structure and gene expression. This report presents the first genome-wide chromatin profiling of histone modifications associated with the C. albicans genome. These epigenomic maps provide an invaluable resource to understand the contribution of chromatin to C. albicans biology and identify aspects of C. albicans chromatin organization that differ from that of other yeasts. IMPORTANCE The fungus Candida albicans is an opportunistic pathogen that normally lives on the human body without causing any harm. However, C. albicans is also a dangerous pathogen responsible for millions of infections annually. C. albicans is such a successful pathogen because it can adapt to and thrive in different environments. Chemical modifications of chromatin, the structure that packages DNA into cells, can allow environmental adaptation by regulating gene expression and genome organization. Surprisingly, the contribution of chromatin modification to C. albicans biology is still largely unknown. For the first time, we analyzed C. albicans chromatin modifications on a genome-wide basis. We demonstrate that specific chromatin states are associated with distinct regions of the C. albicans genome and identify the roles of the chromatin modifiers Sir2 and Set1 in shaping C. albicans chromatin and gene expression.

Chromatin-Mediated Regulation of Genome Plasticity in Human Fungal Pathogens

“…Sir2-dependent heterochromatin assembles at subtelomeric regions and the rDNA locus where it dynamically represses expression of subtelomeric genes, leading to transcriptional noise and repression of non-coding RNAs originating for the non-trascribed spacer (NTS) regions of the rDNA locus [82,83,84]. While C. albicans Sir2 is largely dispensable for repressing recombination at the rDNA locus, Sir2 represses subtelomeric stability by acting on the subtelomeric recombination hotspot TLO recombination element (TRE) [10].…”

“…While C. albicans Sir2 is largely dispensable for repressing recombination at the rDNA locus, Sir2 represses subtelomeric stability by acting on the subtelomeric recombination hotspot TLO recombination element (TRE) [10]. The DNA damage hallmark γH2A is also enriched across subtelomeric regions and at the rDNA locus, suggesting that these regions undergo frequent DNA damage [83]. It is unknown whether and how these γH2A-enriched regions are continuously repaired and whether DNA damage repair at these sites contributes to C. albicans genome instability.…”

“…Surprisingly, Sir2-dependent hypoacetylated heterochromatin does not mark the MRS repeats. MRSs are assembled into highly acetylated chromatin that is permissive to transcription [82,83]. However, MRS repeats are associated with nucleosomes that lack the active histone mark H3K4 methylation [82,83].…”

To Repeat or Not to Repeat: Repetitive Sequences Regulate Genome Stability in Candida albicans

“…More specifically, γH2A abundance is statistically enriched on 13 of the 16 C. albicans subtelomeres (all except ChrRR, 1R, and 7R). Its conspicuous absence in select subtelomeres is thought to be due to incomplete assembly in the current genome assembly and not the absence of γH2A [75]. These γ-sites mark putative recombination-prone genomic loci that are intrinsically more fragile and susceptible to DNA damage [75].…”

Epigenetic dynamics of centromeres and neocentromeres inCryptococcus deuterogattii

“…The pericentric regions are enriched for the euchromatic histone marks H3K9Ac and H4K16Ac, but are hypomethylated at H3K4, a feature of heterochromatic chromatin [15]. Histone H3 is completely depleted at the native centromeres of C. albicans and H3K9 methylation is absent in the C. albicans genome, as this pathway was lost during evolution [16,17]. The mixture of euchromatin and heterochromatin results in reduced expression of genes located in close proximity to the centromeres.…”