*Review* **On and Off: Epigenetic Regulation of** *C. albicans* **Morphological Switches**

**Elise Iracane †, Samuel Vega-Estévez † and Alessia Buscaino \***

Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, CT2 7NJ, UK;

E.Iracane@kent.ac.uk (E.I.); S.Vega-Estevez@kent.ac.uk (S.V.-E.)

**\*** Correspondence: A.Buscaino@kent.ac.uk

† These authors contributed equally to this work.

**Abstract:** The human fungal pathogen *Candida albicans* is a dimorphic opportunistic pathogen that colonises most of the human population without creating any harm. However, this fungus can also cause life-threatening infections in immunocompromised individuals. The ability to successfully colonise different host niches is critical for establishing infections and pathogenesis. *C. albicans* can live and divide in various morphological forms critical for its survival in the host. Indeed, *C. albicans* can grow as both yeast and hyphae and can form biofilms containing hyphae. The transcriptional regulatory network governing the switching between these different forms is complex but well understood. In contrast, non-DNA based epigenetic modulation is emerging as a crucial but still poorly studied regulatory mechanism of morphological transition. This review explores our current understanding of chromatin-mediated epigenetic regulation of the yeast to hyphae switch and biofilm formation. We highlight how modification of chromatin structure and non-coding RNAs contribute to these morphological transitions.

**Keywords:** *Candida albicans*; epigenetic; yeast; chromatin; biofilm; hyphae

### **1. Introduction**

Epigenetics is a popular term first defined by Conrad Waddington in the early 1940s as "the process by which the genotype brings the phenotype into being" [1]. Since then, the meaning of epigenetics has significantly changed. Arthur Riggs defined epigenetics as the study of mitotically and/or meiotically heritable changes in the gene function that are not explained by changes in the DNA sequence [2]. Riggs' definition focuses on heritability: the ability of an epigenetic mark to be passed to subsequent generations of cells and/or organisms. There is no doubt that heritable epigenetics is an important regulatory mechanism. However, this definition excludes many important, not heritable mechanisms often labelled as "epigenetic". For example, post-translation modifications of histone proteins and their effect on gene expression are often described as an epigenetic regulatory mechanism. However, chromatin marks are, in the majority of the cases, transient and not heritable. Likewise, Riggs' definition excludes the role of non-coding RNAs (ncRNAs) in transcription and other DNA-based organisms. To overcome this conundrum, Adrian Bird redefined epigenetics as "the structural adaptation of chromosomal regions to register, signal or perpetuate altered activity states" [3]. This definition focuses on changes in gene function that are independent of changes in the underlying DNA sequence. Importantly, these changes can be heritable or not. Epigenetic regulatory mechanisms include changes in gene expression and chromosome function triggered by chromatin modification, chromatin remodelling and ncRNAs activity [2–8]. In this review, we will adopt Adrian Bird's definition.

Human fungal pathogens are microbial organisms that kill more than 1.5 million people annually and reduce the quality of life of >1 billion people [9]. Additionally, the recent staggering escalation in the number of invasive fungal infections and the emergence

**Citation:** Iracane, E.; Vega-Estévez, S.; Buscaino, A. On and Off: Epigenetic Regulation of *C. albicans* Morphological Switches. *Pathogens* **2021**, *10*, 1463. https://doi.org/ 10.3390/pathogens10111463

Academic Editors: Jonathan Richardson and Lawrence S. Young

Received: 4 August 2021 Accepted: 5 November 2021 Published: 11 November 2021

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of antifungal drug resistance poses an ever-increasing threat to human health. Fungal pathogens grow in association with their host, and establishing how these organisms adapt to hostile host environments is key to understanding how they cause life-threatening infections and develop resistance to antifungal drugs.

Chief among human fungal pathogens is *Candida albicans,* a CTG(Ser1)-clade organism in which the CTG codon is translated as serine rather than leucine [10,11]. *C. albicans* colonises almost every organ in the human body, and therefore, it is exposed to rapid environmental changes [12]. Indeed, *C. albicans* is a harmless commensal yeast found in the skin, gut, oral cavity and mucosa [13]. However, this fungal pathogen can become virulent, establishing an extensive range of mucosal and systemic infections. For example, *C. albicans* can cause vulvovaginal candidiasis (VVC), an infection estimated to afflict 75% of all women at least once in their lifetime [14] or candidiasis, systemic infections that can be life-threatening in immunocompromised individuals and are associated with high mortality rates (up to 50%) [9]. Phenotypic plasticity is a critical regulatory mechanism that drives rapid adaptation to hostile host environments. Indeed, environmental changes can induce dramatic morphological changes, and phenotypic switches are critical host adaptation and virulence drivers. For example, *C. albicans* can grow as a single rounded yeast cell or as multicellular hyphae. Yeast cells are critical for host colonisation, early infection and dissemination, while hyphae facilitate tissue invasion and damage [15,16]. Filamentous cells are also crucial for biofilm formation, a highly organised structure that confers resistance to antimicrobial therapies and the host immune response [17]. *C. albicans* cells can also switch between a white and opaque state. White and opaque cells have different appearances, gene expression profiles and mating behaviours [18].

Epigenetic regulatory mechanisms are emerging as essential modulators of *C. albicans'* phenotypic plasticity. Indeed, epigenetic regulation can sense environmental changes leading to the rapid and reversible modulation of gene expression and adaptation to hostile environments. Recently, Qasim et al. [19] reviewed the role of epigenetics in the white– opaque switch extensively. This review will discuss the contribution of epigenetics to *C. albicans* phenotypic plasticity by focusing on the gene-regulation changes in the yeast -hyphae switch and biofilm formation.
