NuA4 histone acetyltransferase activity is required for H4 acetylation on a dosage-compensated monosomic chromosome that confers resistance to fungal toxins

Hironao Wakabayashi,Jeffrey J Hayes,Elena Rustchenko,Michael Bulger,Stephen L Welle,Christopher Tucker,Anatoliy Kravets,Gabor Bethlendy

doi:10.1186/s13072-017-0156-y

Abstract

BackgroundThe major human fungal pathogen Candida albicans possesses a diploid genome, but responds to growth in challenging environments by employing chromosome aneuploidy as an adaptation mechanism. For example, we have shown that C. albicans adapts to growth on the toxic sugar l-sorbose by transitioning to a state in which one chromosome (chromosome 5, Ch5) becomes monosomic. Moreover, analysis showed that while expression of many genes on the monosomic Ch5 is altered in accordance with the chromosome ploidy, expression of a large fraction of genes is increased to the normal diploid level, presumably compensating for gene dose.ResultsIn order to understand the mechanism of the apparent dosage compensation, we now report genome-wide ChIP-microarray assays for a sorbose-resistant strain harboring a monosomic Ch5. These data show a significant chromosome-wide elevation in histone H4 acetylation on the mCh5, but not on any other chromosome. Importantly, strains lacking subunits of the NuA4 H4 histone acetyltransferase complex, orthologous to a complex previously shown in Drosophila to be associated with a similar gene dosage compensation mechanism, did not show an increase in H4 acetylation. Moreover, loss of NuA4 subunits severely compromised the adaptation to growth on sorbose.ConclusionsOur results are consistent with a model wherein chromosome-wide elevation of H4 acetylation mediated by the NuA4 complex plays a role in increasing gene expression in compensation for gene dose and adaption to growth in a toxic environment.

Highlights

The major human fungal pathogen Candida albicans possesses a diploid genome, but responds to growth in challenging environments by employing chromosome aneuploidy as an adaptation mechanism
Acetylation of H4 and H3 on aneuploid chromosomes in C. albicans We first asked whether histone H4 acetylation patterns across the genome are altered in the well-characterized sorbose-resistant strain Sor125(55) containing a monosomic chromosome 5 (Ch5) and a trisomic Ch4/7b, compared to the normal diploid parental strain (Fig. 1a)
We performed chromatin immunoprecipitation (ChIP)-Chip using an antibody specific for H3 acetylated at the transcription-related sites K9 and K14 and found that H3 acetylation on Ch5 appeared similar to that found on all other disomic chromosomes, exhibiting a sporadic pattern of increases and decreases at various loci in the mutant compared to the parental strain

Summary

Introduction

The major human fungal pathogen Candida albicans possesses a diploid genome, but responds to growth in challenging environments by employing chromosome aneuploidy as an adaptation mechanism. These observations led us to propose that in C. albicans, transcriptional compensation for gene dose serves to facilitate the formation and maintenance of aneuploid chromosome states that are required for survival in adverse environments [7]. While the final number of regulatory genes is yet to be determined, some are involved in cell wall biosynthesis, while others important to the S ou+ and drug susceptibility phenotypes are subjects of antisense regulation [9,10,11]. Despite these advancements, little is known about the formation and maintenance of the monosomic Ch5 state

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