Functional genomic analysis reveals shared transcriptional targets of Tac1a and Tac1b in Candidozyma auris, indicating distinct evolutionary roles in driving antifungal azole resistance.
Key Points
To determine the respective regulatory functions and evolutionary roles of the tandem transcription factors Tac1a and Tac1b in mediating azole resistance in Candidozyma auris.
Generated hyperactivated Tac1a mutants via tagging to assess fluconazole susceptibility compared to Tac1b activation.
Performed chromatin endogenous cleavage sequencing (ChEC-seq) to identify genome-wide target genes and DNA-binding motifs for Tac1a and Tac1b.
Analyzed promoter binding hierarchy and attempted selection of gain-of-function mutations in Tac1a.
Hyperactivation of Tac1a markedly decreased fluconazole susceptibility to a degree similar to Tac1b hyperactivation.
ChEC-seq revealed that Tac1a and Tac1b recognize an identical DNA-binding motif and share downstream targets, including the CDR1 efflux pump and transcription factors Zcf13 and Mrr1b.
Tac1a binds the TAC1b promoter to act upstream in the regulatory cascade, while gain-of-function resistance mutations evolve specifically in Tac1b.