Biased eviction of variant histone H3 nucleosomes triggers biofilm growth in Candida albicans

Abstract

ABSTRACT Candida albicans is an opportunistic human pathogen that colonizes the gastrointestinal and genitourinary tracts of healthy individuals. C. albicans yeast cells can switch to filamentous forms. On biotic and abiotic surfaces, the planktonic free-floating yeast cells often form biofilms, a multi-drug-resistant three-dimensional community of yeast and filamentous cells. While alterations in gene expression patterns during planktonic to biofilm growth transitions in C. albicans have been studied, the underlying molecular mechanisms largely remain unexplored. Previously, we identified a histone H3 variant (H3V CTG ), which acts as a negative regulator of biofilm growth in C. albicans . In the current study, we performed genome-wide profiling of H3V CTG nucleosomes in C. albicans planktonic cells and found them to be enriched at promoter regions. In planktonic cells, H3V CTG -enriched regions are mostly devoid of histone H3 post-translational modifications that allow active transcription, thus strengthening the role of H3V CTG as a negative regulator of biofilm formation. By combining genome-wide transcriptional alterations, nucleosome positioning (MNase-seq), and DNA accessibility (ATAC-seq) assays, we show a significant reduction in the total number of nucleosomes in biofilm cells as compared to planktonic cells indicating a more open chromatin state during biofilm growth. Finally, we propose that H3V CTG -nucleosome eviction at promoters of biofilm-relevant genes in biofilm-grown cells contributes to achieve the open chromatin state by facilitating easy promoter access of master regulators (activators and repressors) for modulation of gene expression observed during growth phase transitions. IMPORTANCE Candida albicans lives as a commensal in most healthy humans but can cause superficial skin infections to life-threatening systemic infections. C. albicans also forms biofilms on biotic and abiotic surfaces. Biofilm cells are difficult to treat and highly resistant to antifungals. A specific set of genes is differentially regulated in biofilm cells as compared to free-floating planktonic cells of C. albicans . In this study, we addressed how a variant histone H3V CTG , a previously identified negative regulator of biofilm formation, modulates gene expression changes. By providing compelling evidence, we show that biased eviction of H3V CTG nucleosomes at the promoters of biofilm-relevant genes facilitates the accessibility of both transcription activators and repressors to modulate gene expression. Our study is a comprehensive investigation of genome-wide nucleosome occupancy in both planktonic and biofilm states, which reveals transition to an open chromatin landscape during biofilm mode of growth in C. albicans , a medically relevant pathogen.