Abstract
ABSTRACTFungal secondary metabolites are small molecules that exhibit diverse biological activities exploited in medicine, industry and agriculture. Their biosynthesis is governed by co-expressed genes that often co-localize in gene clusters. Most of these secondary metabolite gene clusters are inactive under laboratory conditions, which is due to a tight transcriptional regulation. Modifications of chromatin, the complex of DNA and histone proteins influencing DNA accessibility, play an important role in this regulation. However, tinkering with well-characterised chemical and genetic modifications that affect chromatin alters the expression of only few biosynthetic gene clusters, and thus the regulation of the vast majority of biosynthetic pathways remains enigmatic. In the past, attempts to activate silent gene clusters in fungi mainly focused on histone acetylation and methylation, while in other eukaryotes many other post-translational modifications are involved in transcription regulation. Thus, how chromatin regulates the expression of gene clusters remains a largely unexplored research field. In this review, we argue that focusing on only few well-characterised chromatin modifications is significantly hampering our understanding of the chromatin-based regulation of biosynthetic gene clusters. Research on underexplored chromatin modifications and on the interplay between different modifications is timely to fully explore the largely untapped reservoir of fungal secondary metabolites.
Highlights
The fungal kingdom is the source of a wealth of small bioactive compounds called secondary metabolites (SMs)
Based on the accumulating evidence of the occurrence and abundance of these additional histone post-translational modifications (PTMs) and DNA methylation, together with the observation that only few gene clusters seem to be solely regulated by histone acetylation and methylation, it is timely to shift focus and study underexplored chromatin modifications to unravel the complex regulation of SM gene clusters expression
The discovery of chromatin as a central regulator of fungal SM production significantly impacted on our understanding of the complex transcriptional regulation of biosynthetic gene clusters
Summary
The fungal kingdom is the source of a wealth of small bioactive compounds called secondary metabolites (SMs). Methylation of H3K4 and H3K36 seems to activate transcription through the recruitment of HATs at specific methylated nucleosomes (Martin et al 2006; Ginsburg et al 2014; Martin et al 2017) besides histone acetylation and methylation, other PTMs such as butyrylation, propionylation, phosphorylation, proline isomerisation, sumoylation, and ubiquitination have been reported in fungi (Table 1) (De Souza et al 2000; Hsu et al 2000; Robzyk, Recht and Osley 2000; Ahn et al 2005b; Nathan et al 2006; Zhang et al 2009; Strauss and Reyes-Dominguez 2011; Trujillo et al 2011; Xie et al 2012; Hasim et al 2013; Monneau et al 2013; Andrews et al 2016), suggesting that these additional PTMs can influence chromatin accessibility and thereby transcriptional regulation.
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