Diversification of DNA binding specificities enabled SREBP transcription regulators to expand the repertoire of cellular functions that they govern in fungi

The Sterol Regulatory Element Binding Proteins (SREBPs) are basic-helix-loop-helix transcription regulators that control the expression of sterol biosynthesis genes in higher eukaryotes and some fungi. Surprisingly, SREBPs do not regulate sterol biosynthesis in the ascomycete yeasts (Saccharomycotina) as this role was handed off to an unrelated transcription regulator in this clade. The SREBPs, nonetheless, expanded in fungi such as the ascomycete yeasts Candida spp., raising questions about their role and evolution in these organisms. Here we report that the fungal SREBPs diversified their DNA binding preferences concomitantly with an expansion in function. We establish that several branches of fungal SREBPs preferentially bind non-palindromic DNA sequences, in contrast to the palindromic DNA motifs recognized by most basic-helix-loop-helix proteins (including SREBPs) in higher eukaryotes. Reconstruction and biochemical characterization of the likely ancestor protein suggest that an intrinsic DNA binding promiscuity in the family was resolved by alternative mechanisms in different branches of fungal SREBPs. Furthermore, we show that two SREBPs in the human commensal yeast Candida albicans drive a transcriptional cascade that inhibits a morphological switch under anaerobic conditions. Preventing this morphological transition enhances C. albicans colonization of the mammalian intestine, the fungus’ natural niche. Thus, our results illustrate how diversification in DNA binding preferences enabled the functional expansion of a family of eukaryotic transcription regulators.
Author summary Transcription regulation is the primary step by which most cells control the expression of their genes. At its core, this process is mediated by proteins (transcription regulators) that bind to short DNA regulatory elements in a sequence-specific manner. Recent research in multiple model organisms ranging from vertebrates to unicellular yeasts has revealed that evolutionary changes either in the DNA regulatory elements or in the transcription regulators themselves underlie the origin of many traits such as morphological innovations or the ability to colonize new environments. While the effects of mutations that abolish or create DNA regulatory elements are straightforward to rationalize, understanding what sort of modifications the transcription regulators undergo and how these changes impinge upon the regulatory circuitry of the organism remains a key challenge. Here we investigate the mechanisms whereby a family of conserved transcription regulators diversified the biological functions that they control. While in most eukaryotes this family of regulators governs lipid biosynthesis, three members of the family in the human pathogen Candida albicans have acquired different functions, some of which contribute to the ability of this yeast to reside in the human host and cause disease.