When first discovered, the gene LaeA was thought to be a master switch for silencing of several NRPS secondary metabolite gene clusters in Aspergillus. NRPS and PKS are important genes in filamentous fungi as they produce many compounds that likely help fungi compete in the ecological niche mycotoxins (e.g. aflatoxin, gliotoxin), plant hormone (e.g. Gibberellin), and a potential wealth of additional undiscovered activities.
A recent paper from Nancy Keller’s lab entitled Transcriptional Regulation of Chemical Diversity in Aspergillus fumigatus by LaeA has followed up previous studies with whole genome expression profiling of a LaeA knockout strain to explore the breadth of the genome that is regulated by this transcriptional regulator. The exact mechanism of LaeA silencing is not fully understood although it is thought to act via chromatin remodeling. There was some debate as to whether or not the pathway regulated production of a specific toxin that regulates virulence or if it was master regulator that controlled several different metabolite production pathways. Î”LaeA was hypovirulent but yet individual knockout of a known toxin like the gliotoxin NRPS did not show attenuated virulence. So LaeA much be regulating additional genes besides gliotoxin.
The Perrin et al study sought to explore this relationship through whole genome expression profiling. They found that LaeA influences the expression (positively or negatively) of at least 9.5% of the genome and that it positively controls the expression of 20-40% of the major secondary metabolite pathways including not only NRPSs, but Polyketide synthases (PKS), and P450 monooxygenases genes. This helps resolve some of the conflicting results from different knockout experiments.
It also provides an interesting window into how these genes and gene clusters may have evolved. There aren’t a lot of good examples of global regulation by chromatin silencing in fungi. The MAT HML and HMR cassette silencing in Saccharomyces is one example and telomeric and centromeric silencing are another other. Future work here is will help dissect both the mechanism of silencing and the potential role it has in regulation of secondary metabolite genes and virulence factors in filamentous pathogens.