Echinocandin Adaptation in Candida albicans Is Accompanied by Altered Chromatin Accessibility at Gene Promoters and by Cell Wall Remodeling

TL;DR

This study explores how Candida albicans adapts to echinocandin drugs by changing chromatin accessibility and cell wall structure.

Contribution

The study reveals genome-wide chromatin accessibility changes and cell wall remodeling in Candida albicans during echinocandin adaptation.

Findings

Drug adaptation is linked to chromatin accessibility changes in gene promoters.

Promoter regions show enriched binding motifs for zinc finger and basic leucine zipper transcription factors.

ECN-adapted mutants exhibit cell wall remodeling with increased chitin and cell surface exposure.

Abstract

Infections by the major opportunistic pathogen of human Candida albicans are commonly treated with echinocandin (ECN) drugs. However, C. albicans can adapt to grow in the presence of certain amounts of ECNs. Prior studies by several laboratories have defined multiple genes, as well as mechanisms involving induced aneuploidy, that can govern this. Still, the mechanisms of ECN adaptation are not fully understood. Here, we use genome-wide profiling of chromatin accessibility by ATAC-seq to determine if ECN adaptation is reflected in changes in the chromatin landscape in the absence of aneuploidy. We find that drug adaptation is coupled with multiple changes in chromatin accessibility genome-wide, which occur predominantly in gene promoter regions. Areas of increased accessibilities in promoters are enriched with the binding motifs for at least two types of transcription factors: zinc finger and basic leucine zipper. We also find that chromatin changes are often associated with differentially expressed genes including genes with functions relevant to the ECN-adapted phenotype, such as cell wall biosynthesis. Consistent with this, we find that the cell wall is remodeled in ECN-adapted mutants, with chitin up and glucan down and increased cell surface exposure. A full understanding of ECN adaptation processes is of critical importance for the prevention of clinical resistance.

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