Regulation of secondary metabolism by chromatin structure and epigenetic codes.

Chromatin, composed of DNA wrapped around an octamer of histones, is the relevant substrate for all genetic processes in eukaryotic nuclei. Changes in chromatin structure are associated with the activation and silencing of gene transcription and reversible post-translational modifications of histones are now known to direct chromatin structure transitions. Recent studies in several fungal species have identified a chromatin-based regulation of secondary metabolism (SM) gene clusters representing an upper-hierarchical level for the coordinated control of large chromosomal elements. Regulation by chromatin transition processes provides a mechanistic model to explain how different SM clusters located at dispersed genomic regions can be simultaneously silenced during primary metabolism. Activation of SM clusters has been shown to be associated with increased acetylation of histones H3 and H4 and, consequently, inhibition of histone de-acetylase activities also leads to increased production of secondary metabolites. New findings suggest that SM clusters are silenced by heterochromatic histone marks and that the "closed" heterochromatic structures are reversed during SM activation. This process is mediated by the conserved activator of SM, LaeA. Despite the increase in knowledge about these processes, much remains to be learned from chromatin-level regulation of SM. For example, which proteins "position" the chromatin restructuring signal onto SM clusters or how exactly LaeA works to mediate the low level of heterochromatic marks inside different clusters remain open questions. Answers to these and other chromatin-related questions would certainly complete our understanding of SM gene regulation and signaling and, because for many predicted SM clusters corresponding products have not been identified so far, anti-silencing strategies would open new ways for the identification of novel bioactive substances.