Heterochromatic marks are associated with the repression of secondary metabolism clusters in Aspergillus nidulans

Abstract

Fungal secondary metabolites are important bioactive compounds but the conditions leading to expression of most of the putative secondary metabolism (SM) genes predicted by fungal genomics are unknown. Here we describe a novel mechanism involved in SM-gene regulation based on the finding that, in Aspergillus nidulans, mutants lacking components involved in heterochromatin formation show de-repression of genes involved in biosynthesis of sterigmatocystin (ST), penicillin and terrequinone A. During the active growth phase, the silent ST gene cluster is marked by histone H3 lysine 9 trimethylation and contains high levels of the heterochromatin protein-1 (HepA). Upon growth arrest and activation of SM, HepA and trimethylated H3K9 levels decrease concomitantly with increasing levels of acetylated histone H3. SM-specific chromatin modifications are restricted to genes located inside the ST cluster, and constitutive heterochromatic marks persist at loci immediately outside the cluster. LaeA, a global activator of SM clusters in fungi, counteracts the establishment of heterochromatic marks. Thus, one level of regulation of the A. nidulans ST cluster employs epigenetic control by H3K9 methylation and HepA binding to establish a repressive chromatin structure and LaeA is involved in reversal of this heterochromatic signature inside the cluster, but not in that of flanking genes.

Fungal S-adenosylmethionine synthetase and the control of development and secondary metabolism in Aspergillus nidulans

“…Histone-3 trimethylation at lysine 9 had been found to be associated with the repression of secondary metabolism clusters in A. nidulans. LaeA is presumably involved in reversal of this heterochromatin signature inside the cluster (Reyes-Dominguez et al, 2010). The interaction of SasA with histone-2B is consistent with the finding that histone-2B can stimulate histone methyltransferase activity when modified at lysine 34 by ubiquitin (Wu et al, 2011).…”

“…An additional role of LaeA is its requirement for Hülle cell formation (Sarikaya Bayram et al, 2010). LaeA carries a conserved SAM-binding site typical for nuclear protein methyltransferases (Bok and Keller, 2004;Kozbial and Mushegian, 2005) and there is accumulating evidence for an epigenetic control function of LaeA by chromatin remodeling (Reyes-Dominguez et al, 2010). A misregulation of the SAM synthetase encoding gene in A. nidulans might therefore affect development and secondary metabolism.…”

Bacteria-induced natural product formation in the fungus Aspergillus nidulans requires Saga/Ada-mediated histone acetylation

“…Recently, ReyesDominguez et al (28) showed that acetylation of these H3 residues in the promoter region of the sterigmatocystin biosynthesis regulatory gene aflR was increased when the fungus was shifted to sterigmatocystin production conditions. However, a high level of acetylation did not necessarily lead to a high expression of cluster genes.…”

Transcription of Genes in the Biosynthetic Pathway for Fumonisin Mycotoxins Is Epigenetically and Differentially Regulated in the Fungal Maize Pathogen Fusarium verticillioides

“…This suggests that under noninducing conditions the acetylation status of histones in this region is kept relatively low by constitutive, reciprocal activities of HATs and HDACs and that FB-inducing conditions cause a shift in this equilibrium. That histone acetylation is involved in the regulation of the aflatoxin cluster in A. parasiticus and of the sterigmatocystin cluster in A. nidulans was also demonstrated by ChIP assays (22,25). The HDAC-encoding gene HDF1 of Fusarium graminearum was also very recently shown to influence deoxynivalenol production, along with virulence, sexual and asexual reproduction, and development (12).…”

“…Recent studies have begun to identify molecular players in chromatin remodeling in fungi, which seems to impact SM synthesis more extensively than primary cell functions. Epigenetic control of fungal SM has been confirmed for sterigmatocystin, penicillin, and terrequinone A (22,28). Those studies highlighted the importance, in fungal SM, of reversible posttrans-lational modifications of histones (the proteins around which DNA is wrapped to form nucleosomes) and of the enzymes that carry out such modifications (30).…”