Secondary metabolism in fungi: does chromosomal location matter?

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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.

Introduction

For many years it has been known that chromosomal location and histone modification have profound effects on gene transcription in a variety of organisms from yeast to humans. Filamentous fungi produce many bioactive small molecules, or secondary metabolites, that range from beneficial antibiotics to harmful toxins. Genes responsible for the production of these secondary metabolites are typically clustered and coregulated [1]. Interestingly, the order and location of biosynthetic genes within a cluster is important for their regulation. Additionally, secondary metabolite gene clusters have a tendency to be located near the ends of chromosomes in areas termed subtelomeric [2••, 3•]  a region where chromatin modifiers impact transcription of these clustered genes. Here we review the importance of location, both specific locations of genes within a cluster, the chromosomal location of the entire cluster itself, and putative epigenetic forces on the genetic regulation of secondary metabolite gene clusters in fungi. We offer a view that secondary metabolite clusters are located in regions of facultative heterochromatin, which can be silenced and activated by both canonical and novel chromatin-mediated mechanisms.

Section snippets

Hallmarks of gene silencing in fungi

Eukaryotic organisms have evolved orchestrated mechanisms to regulate their large gene networks for proper development and appropriate environmental responses. In recent years, much interest has been focused on epigenetic and small RNA regulation of gene expression. Common to all eukaryotes, fungi possess several cellular devices important in gene silencing and activation. Early research in Saccharomyces cerevisiae identified the silent mating type loci (HML/HMR), which subsequently opened the

Regulation of secondary metabolite gene clusters in fungi

An unexpected finding upon inspection of several fungal genomes was the presence of vast numbers of secondary metabolite gene clusters [19]. Although most remain undefined, research on select gene clusters is quite robust and serves to illustrate several important points on the regulation of secondary metabolite gene clusters. The reader is directed to recent reviews detailing nonheterochromatic regulatory mechanisms employed to regulate these clusters [1, 19, 20, 21]. Briefly, many clusters

Chromosomal location of secondary metabolite gene clusters

As mentioned earlier, methylation of H3K9 is associated with heterochromatin, while methylation of H3K4 is more commonly associated with euchromatin and transcription. However, the COMPASS complex, which methylates H3K4 in yeast, is also associated with homothallic mating type silencing, ribosomal DNA silencing, and subtelomeric gene expression in this fungus [18]. Paralleling these observations, it was shown that a mutant defective in a component of the COMPASS complex activates silent

Conclusions

This review highlights work suggestive of epigenetic regulation of secondary metabolite gene clusters in filamentous fungi. Recently there has been an increase in the number of examples of gene cluster regulation mediated by chromatin remodeling enzymes, including chemical epigenetic approaches. These studies reveal the importance of positional effects, both location effects within a cluster and chromosomal location effects on cluster regulation. Future studies are warranted to tease out the

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

This work was in part funded by the National Institute of Health (1R01 AI065728-01) to NPK.

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