The Chromatin of Candida albicans Pericentromeres Bears Features of Both Euchromatin and Heterochromatin

Freire-Benéitez, Verónica; Price, R. Jordan; Buscaino, Alessia

doi:10.3389/fmicb.2016.00759

Cited by 14 publications

(11 citation statements)

References 43 publications

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“…Pericentromeric regions in C . albicans have elevated levels of H4K16 acetylation relative to the central core region [ 46 ]. Treatment with 2mM nicotinamide increased the relative level of H4K16 acetylation within the centromeric central core ( S8A Fig ).…”

Section: Resultsmentioning

confidence: 99%

Neocentromeres Provide Chromosome Segregation Accuracy and Centromere Clustering to Multiple Loci along a Candida albicans Chromosome

et al. 2016

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Assembly of kinetochore complexes, involving greater than one hundred proteins, is essential for chromosome segregation and genome stability. Neocentromeres, or new centromeres, occur when kinetochores assemble de novo, at DNA loci not previously associated with kinetochore proteins, and they restore chromosome segregation to chromosomes lacking a functional centromere. Neocentromeres have been observed in a number of diseases and may play an evolutionary role in adaptation or speciation. However, the consequences of neocentromere formation on chromosome missegregation rates, gene expression, and three-dimensional (3D) nuclear structure are not well understood. Here, we used Candida albicans, an organism with small, epigenetically-inherited centromeres, as a model system to study the functions of twenty different neocentromere loci along a single chromosome, chromosome 5. Comparison of neocentromere properties relative to native centromere functions revealed that all twenty neocentromeres mediated chromosome segregation, albeit to different degrees. Some neocentromeres also caused reduced levels of transcription from genes found within the neocentromere region. Furthermore, like native centromeres, neocentromeres clustered in 3D with active/functional centromeres, indicating that formation of a new centromere mediates the reorganization of 3D nuclear architecture. This demonstrates that centromere clustering depends on epigenetically defined function and not on the primary DNA sequence, and that neocentromere function is independent of its distance from the native centromere position. Together, the results show that a neocentromere can form at many loci along a chromosome and can support the assembly of a functional kinetochore that exhibits native centromere functions including chromosome segregation accuracy and centromere clustering within the nucleus.

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Section: Resultsmentioning

confidence: 99%

Neocentromeres Provide Chromosome Segregation Accuracy and Centromere Clustering to Multiple Loci along a Candida albicans Chromosome

et al. 2016

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“…Regulation of chromatin structure plays critical roles in regulating C. albicans gene expression and genome instability (39–42). However, comprehensive profiling of histone modifications across the whole C.…”

Section: Introductionmentioning

confidence: 99%

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

Price

Weindling

Berman

et al. 2019

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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.

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“…In this study, we hypothesize that the miniscule levels of CENPA at the pericentromeres, which may be undetectable by less-sensitive methods like ChIP-seq, is important to activate a neocentromere at CEN-proximal regions in the absence of the native CEN. A previous attempt to characterize the pericentromeres in C. albicans claimed that a pericentric insertion of URA3 imposes a weak transcriptional repression (Freire-Benéitez et al 2016). These assays were based on growth phenotypes and qRT-PCR analysis, making them less sensitive.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, there is no functional evidence for the existence of a pericentric boundary element to restrict CENPA in C. albicans, as seen in the case of CENs in S. pombe (Karpen and Allshire 1997;Allshire and Ekwall 2015). Unlike S. pombe, the genome of C. albicans does not encode an HP1/Swi6-like protein, an H3K9 methyltransferase like Clr4, and components of a fully functional RNAi machinery (Freire-Benéitez et al 2016). There is no evidence of DNA methylation at the CEN DNA in C. albicans (Baum et al 2006;Mishra et al 2011).…”

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confidence: 99%

Cis- andTrans-chromosomal Interactions Define Pericentric Boundaries in the Absence of Conventional Heterochromatin

et al. 2019

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The diploid budding yeast Candida albicans harbors unique CENPA-rich 3-to 5-kb regions that form the centromere (CEN) core on each of its eight chromosomes. The epigenetic nature of these CENs does not permit the stabilization of a functional kinetochore on an exogenously introduced CEN plasmid. The flexible nature of such centromeric chromatin is exemplified by the reversible silencing of a transgene upon its integration into the CENPA-bound region. The lack of a conventional heterochromatin machinery and the absence of defined boundaries of CENPA chromatin makes the process of CEN specification in this organism elusive. Additionally, upon native CEN deletion, C. albicans can efficiently activate neocentromeres proximal to the native CEN locus, hinting at the importance of CEN-proximal regions. In this study, we examine this CEN-proximity effect and identify factors for CEN specification in C. albicans. We exploit a counterselection assay to isolate cells that can silence a transgene when integrated into the CEN-flanking regions. We show that the frequency of reversible silencing of the transgene decreases from the central core of CEN7 to its peripheral regions. Using publicly available C. albicans high-throughput chromosome conformation capture data, we identify a 25-kb region centering on the CENPA-bound core that acts as CEN-flanking compact chromatin (CFCC). Cisand trans-chromosomal interactions associated with the CFCC spatially segregates it from bulk chromatin. We further show that neocentromere activation on chromosome 7 occurs within this specified region. Hence, this study identifies a specialized CEN-proximal domain that specifies and restricts the centromeric activity to a unique region. KEYWORDS centromere; CENPA; Hi-C; Candida albicans; neocentromere I N a majority of eukaryotes, centromere (CEN) specification is fulfilled by the assembly of the histone H3 variant, CENPA, and subsequent kinetochore stabilization. In most fungal species, CENs extend over to a region on every chromosome, ranging in sizes from 3 to 300 kb (Friedman and Freitag 2017), which are categorized as short regional or long regional CENs. The CENs in the Candida species are one of the most well-studied short regional CENs. Candida albicans has unique 3-5 kb CENPA-bound CEN DNA (Sanyal et al. 2004), as does C. dubliniensis (Padmanabhan et al. 2008) and C. lusitaniae (Kapoor et al. 2015). On the other hand, the 10-to 11-kb CENs in C. tropicalis consist of a 2-to 5-kb central core flanked by inverted repeats (Chatterjee et al. 2016). The 40-to 110-kb-long regional CENs of Schizosaccharomyces pombe contain a 10-to 14-kb-long CENPAbound region flanked by outer pericentric repeats (Clarke et al. 1986). The filamentous yeast Neurospora crassa harbors 150-300 kb of heterochromatic CENPA-rich DNA (Smith et al. 2011). Among the basidiomycetes, Cryptococcus neoformans contain 27-65 kb of transposon-rich CENPA-bound DNA sequences (Yadav et al. 2018). Evidently, regional CENs in fungi do not

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The Chromatin of Candida albicans Pericentromeres Bears Features of Both Euchromatin and Heterochromatin

Cited by 14 publications

References 43 publications

Neocentromeres Provide Chromosome Segregation Accuracy and Centromere Clustering to Multiple Loci along a Candida albicans Chromosome

Neocentromeres Provide Chromosome Segregation Accuracy and Centromere Clustering to Multiple Loci along a Candida albicans Chromosome

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

Cis- andTrans-chromosomal Interactions Define Pericentric Boundaries in the Absence of Conventional Heterochromatin

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