title: The fumagillin gene cluster, an example of hundreds of genes under veA control in Aspergillus fumigatus.
abstract: Aspergillus fumigatus is the causative agent of invasive aspergillosis, leading to infection-related mortality in immunocompromised patients. We previously showed that the conserved and unique-to-fungi veA gene affects different cell processes such as morphological development, gliotoxin biosynthesis and protease activity, suggesting a global regulatory effect on the genome of this medically relevant fungus. In this study, RNA sequencing analysis revealed that veA controls the expression of hundreds of genes in A. fumigatus, including those comprising more than a dozen known secondary metabolite gene clusters. Chemical analysis confirmed that veA controls the synthesis of other secondary metabolites in this organism in addition to gliotoxin. Among the secondary metabolite gene clusters regulated by veA is the elusive but recently identified gene cluster responsible for the biosynthesis of fumagillin, a meroterpenoid known for its anti-angiogenic activity by binding to human methionine aminopeptidase 2. The fumagillin gene cluster contains a veA-dependent regulatory gene, fumR (Afu8g00420), encoding a putative C6 type transcription factor. Deletion of fumR results in silencing of the gene cluster and elimination of fumagillin biosynthesis. We found expression of fumR to also be dependent on laeA, a gene encoding another component of the fungal velvet complex. The results in this study argue that veA is a global regulator of secondary metabolism in A. fumigatus, and that veA may be a conduit via which chemical development is coupled to morphological development and other cellular processes.
authors.affiliation: Department of Biological Sciences, Northern Illinois University, DeKalb, Illinois, United States of America.
authors.forename: Sourabh
authors.initials: S
authors.lastname: Dhingra
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Lind
authors.forename: Hsiao-Ching
authors.initials: HC
authors.lastname: Lin
authors.forename: Yi
authors.initials: Y
authors.lastname: Tang
authors.forename: Antonis
authors.initials: A
authors.lastname: Rokas
authors.forename: Ana M
authors.initials: AM
authors.lastname: Calvo
mesh_terms: D001228:Aspergillosis / Q000382:microbiology*; D001232:Aspergillus fumigatus / Q000235:genetics* / Q000378:metabolism; D003510:Cyclohexanes / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000235:genetics* / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D006801:Humans; D005810:Multigene Family; D012717:Sesquiterpenes / Q000378:metabolism
chemical_list: D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D005656:Fungal Proteins; D012717:Sesquiterpenes; C026211:fumagillin