A Recently Evolved Transcriptional Network Controls Biofilm Development in Candida albicans

Abstract

A biofilm is an organized, resilient group of microbes where individual cells acquire properties, such as drug resistance, that are distinct from those observed in suspension cultures. Here we describe and analyze the transcriptional network controlling biofilm formation in the pathogenic yeast Candida albicans, whose biofilms are a major source of medical device-associated infections. We have combined genetic screens, genome-wide approaches, and two in vivo animal models to describe a master circuit controlling biofilm formation, composed of six transcription regulators that form a tightly woven network with ~1000 target genes. Evolutionary analysis indicates that the biofilm network has rapidly evolved: genes in the biofilm circuit are significantly weighted towards genes that arose relatively recently with ancient genes being underrepresented. This circuit provides a framework for understanding many aspects of biofilm formation by C. albicans in a mammalian host. It also provides insights into how complex cell behaviors can arise from the evolution of transcription circuits.

(1‐aryloxy‐2‐hydroxypropyl)‐phenylpiperazine derivatives suppress Candida albicans virulence by interfering with morphological transition

“…6B). To explore the working model of piperazine derivatives on the morphological transition of C. albicans , we continued to test whether these compounds interfered with the signalling pathways of the hyphae development process (Sudbery et al ., 2004; Lu et al ., 2011; Shareck and Belhumeur, 2011; Nobile et al ., 2012). Real‐time PCR analysis showed that exogenous addition of the leading compound 28e inhibited the expression levels of CDC35, EFG1, TEC1 and HWP1, which are regulators involved in the cAMP‐PKA pathways (Fig.…”

A comprehensive functional portrait of two heat shock factor-type transcriptional regulators involved in Candida albicans morphogenesis and virulence

“…Ndt80p occupies the promoter region of roughly a quarter of total C. albicans genes under yeast-form growth conditions, suggesting wide functions for Ndt80p [57]. Indeed, it was shown that Ndt80p regulates different processes including drug resistance, cell separation, hyphal differentiation, biofilm formation and virulence [54,57,58]. Importantly, the C. albicans ndt80D/ndt80D mutant is unable to form true hyphae under different filamentation-inducing conditions and, in the presence of serum at 37uC, it fails to activate the expression of HSGs, including HWP1, ECE1, RBT4, ALS3, HYR1 and SAP4 [58], all directly regulated by Sfl2p (Figure 6), as well as the transcription factor-encoding genes TEC1 and UME6 which are both directly modulated by Sfl1p and Sfl2p ( Figure 6).…”

“…Although Efg1p binding is altered upon hyphal induction, Efg1p co-immunoprecipitated with Sfl2p ( Figure 9B) at 37uC in Lee's medium, which may explain Sfl2p dependency on EFG1 to regulate morphogenesis under certain conditions. Nobile et al elegantly showed that an intricate transcriptional network involving Ndt80p, Efg1p, Brg1p, Bcr1p, Rob1p and Tec1p controls biofilm development in C. albicans [54]. Interestingly, with the exception of BCR1, all genes encoding these regulators are direct targets of Sfl1p or Sfl2p ( Figure 6 and [54]).…”

“…Moreover, Sfl2p directly upregulated genes encoding (or predicted to encode) transcription factors, including FCR3, encoding a positive regulator of C. albicans adherence [52], orf19.217, encoding a positive regulator of hyphal growth [41] and RFX2, encoding a regulator of DNA damage response, adhesion and virulence [53]. On the other hand, Sfl2p directly downregulated the expression of transcription factors SFL1, ECM22, ROB1, encoding a regulator of biofilm formation [54], and many genes involved or predicted to be involved in cell wall integrity (EAP1, FUN31, SIM1, PIR1 and RHD3) as well as genes encoding or predicted to encode permeases or transporters (PHO86, putative inorganic phosphate transporter; HGT1, high-affinity glucose transporter; FLC3, putative heme transporter; HIP1 and orf19.7566, putative amino acid transporters).…”

“…Two independent motif discovery algorithms, the RSA-tools (RSAT) peak-motifs (http:// rsat.ulb.ac.be/rsat/, [55]) and SCOPE (genie.dartmouth.edu/ scope/, [56]) were used (See Materials and Methods for details). Strikingly, the highest scoring motifs in Sfl1p-enriched sequences included the Ndt80p (59-ttACACAAA-39, mid-sporulation element, lowercase letters represent nucleotides with low-frequency occurrence) and the Efg1p (59-taTGCAta-39) binding motifs [51,54,57] in addition to two high scoring motifs, 59-TtCtaGaA-39 and 59-TCGAACCC-39, carrying GAA triplets that are characteristic of HSEs ( Figure 8A, shown are motifs found using the global overrepresentation of words relative to control sequences, significance index score (i.e. 2log 10 E-value) .10 for RSAT analyses and .25 for SCOPE analyses).…”