Appl Microbiol Biotechnol (2012) 95:1389–1404 DOI 10.1007/s00253-012-4208-8 MINI-REVIEW The chromatin code of fungal secondary metabolite gene clusters Agnieszka Gacek & Joseph Strauss Received: 16 February 2012 / Revised: 24 May 2012 / Accepted: 24 May 2012 / Published online: 20 July 2012 # The Author(s) 2012. This article is published with open access at Springerlink.com Abstract Secondary metabolite biosynthesis genes in fungi are usually physically linked and organized in large gene clusters. The physical linkage of genes involved in the same biosynthetic pathway minimizes the amount of regulatory steps necessary to regulate the biosynthetic machinery and thereby contributes to physiological economization. Regu- lation by chromatin accessibility is a proficient molecular mechanism to synchronize transcriptional activity of large genomic regions. Chromatin regulation largely depends on DNA and histone modifications and the histone code hy- pothesis proposes that a certain combination of modifica- tions, such as acetylation, methylation or phosphorylation, is needed to perform a specific task. A number of reports from several laboratories recently demonstrated that fungal secondary metabolite (SM) biosynthesis clusters are con- trolled by chromatin-based mechanisms and histone acetyl- transferases, deacetylases, methyltransferases, and proteins involved in heterochromatin formation were found to be involved. This led to the proposal that establishment of repressive chromatin domains over fungal SM clusters un- der primary metabolic conditions is a conserved mechanism that prevents SM production during the active growth phase. Consequently, transcriptional activation of SM clusters requires reprogramming of the chromatin landscape and A. Gacek : J. Strauss (*) Fungal Genetics and Genomics Unit, Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Science, University and Research Center—Campus Tulln, 3430 Tulln/Donau, Austria e-mail: joseph.strauss@boku.ac.at J. Strauss Health and Environment Department, Austrian Institute of Technology, University and Research Center—Campus Tulln, 3430 Tulln/Donau, Austria replacement of repressive histone marks by activating marks. This review summarizes recent advances in our understanding of chromatin-based SM cluster regulation and highlights some of the open questions that remain to be answered before we can draw a more comprehensive picture. Keywords Secondary metabolism . Chromatin . Aspergillus . Histone modifications Introduction Recent editions of natural products databases, such as “Anti- base” contain structures and chemical characteristics of al- most 39,000 different microbial “secondary metabolites” (SMs) (Laatsch 2011). Such impressive variety of small organic molecules is produced by fungi and bacteria usually only under special growth conditions termed “secondary metabolism”. This physiological state follows “primary me- tabolism” which is essential for growth, normal develop- ment, and reproduction. In contrast, secondary metabolism is not immediately essential for the organism, but, through the production of specific metabolites, may influence the competitiveness in natural environments and thus the long- term survival and fecundity of the species. Typical examples of secondary metabolites are pigments, which absorb dam- aging ultraviolet radiation and thus protect the organism against DNA damage and oxidative stress (Brakhage and Liebmann 2005; Ha Huy and Luckner 1979). Other typical fungal SMs are bioactive substances like antibiotics, which restrain microbial competitors (Baquero et al. 2011, Brakhage 1998; Meloni and Schito 1991) and mycotoxins, which have significant impacts on human and animal health (Bennett and Klich 2003; Newberne 1974). Mycotoxins such