Secondary metabolism in fungi: does chromosomal location matter?

Abstract

Filamentous fungi produce a vast array of small molecules called secondary metabolites, which include toxins as well as antibiotics. Coregulated gene clusters are the hallmark of fungal secondary metabolism, and there is a growing body of evidence that suggests regulation is at least, in part, epigenetic. Chromatin-level control is involved in several silencing phenomena observed in fungi including mating type switching, telomere position effect (TPE), silencing of ribosomal DNA, regulation of genes involved in nutrient acquisition, and as presented here, secondary metabolite cluster expression. These phenomena are tied together by the underlying theme of chromosomal location, often near centromeres and telomeres, where facultative heterochromatin plays a role in transcription. Secondary metabolite gene clusters are often located subtelomerically and recently it has been shown that proteins involved in chromatin remodeling, such as LaeA, ClrD, CclA, and HepA mediate cluster regulation.

Figure 1. A proposed model for chromatin mediated control of secondary metabolite gene clusters

Secondary metabolite gene clusters are often flanked by repetitive elements (RE) and located in sub-telomeric regions of the genome. The epigenetic marks of H3K4 methylation (H3K4-CH₃) and general histone acetylation have been shown to be associated with active gene transcription [17]. Thus, histone acetyltransferases (HAT) and the H3K4 methylation protein complex (COMPASS) are involved in initiation of transcription through RNA polymerase II (Pol II) [18]. Environmental stimuli are translated by signal transduction cascades, including but not limited to MAPK and PkaA, to trigger production of secondary metabolites [19]. These signals work independently and dependently through the LaeA containing velvet complex [25,26]. On the other hand, in several eukaryotic systems heterochromatin protein 1 has been shown to bind H3K9 methylation (H3K9-CH₃) and is associated with gene silencing. In Aspergillus nidulans, null mutants of the H3K9 methyltransferase (ClrD) and heterochromatin protein 1 (HepA) result in derepression of the ST gene cluster [40••]. Currently, the genetic components involved in initiation of heterochromatin at secondary metabolite gene clusters is unknown, RNAi mediated heterochromatin formation could function this way as well as DNA binding repressors.