1400 modifications seem to carry out crucial regulatory functions for SM cluster expression. Based on this modification pattern, we can predict that LaeA—in concert with the velvet complex and probably other proteins—is part of a cluster-specific regulatory complex that keeps H3K9 methylation and subse- quent HP1 association low. However, apart from blocking H3K9 methylation or promoting de-methylation and subse- quent reversal of heterochromatic structures, the LaeA-velvet complex must have an additional role in SM gene activation. This can be concluded because deletion of components re- quired for heterochromatin formation, i.e., the clrD H3K9 methyltransferase and hepA, encoding heterochromatin pro- tein 1, only partially restores SM production. The exact mo- lecular mechanism behind this additional function of LaeA is still a matter of speculation and subject to intense research. Further studies are needed to obtain a more detailed picture of the regulatory network that remodels the repres- sive heterochromatin to transcriptionally competent euchro- matin during the secondary metabolism phase. The greatest challenge in deciphering the chromatin code of SM clusters and adjoin regions is the availability of suitable antibodies specific for the large diversity of histone modifications in the studied organism. Although the histone PTMs are con- served structures in all eukaryotes, we can not exclude a priori other modifications or new combinations of known modifications in fungi. In addition, the interaction of the antibody with its epitope during ChIP can potentially be influenced by adjacent PTMs in neighboring amino acids. Therefore, each antibody in use has to be tested for speci- ficity and control strains carrying amino acid changes in the modified residue of histones need to be generated. Some of these changes may not be possible at all because the result- ing strain may not be viable. Moreover, the mutation itself might interfere with primary and secondary metabolite gene expression and therefore complicate interpretation of results. However, the advent of extremely powerful massive parallel sequencing techniques will help to enlarge the picture from specific SM clusters to a genome-wide scale and will pro- vide valuable insights how chromatin structure and histone modifications react to metabolic changes and to mutations or over-expression of crucial regulators. And as the family of sequenced fungal genomes constantly grows, these approaches have the potential to draw out exciting data for comparative chromatin studies. From the few well-studied model pathways, such as ST, PEN or the ORS cluster, we have already learnt that all clusters are controlled by a chromatin-based mechanism, but that the exact mode of control can differ significantly between the individual clusters within one organism. Even more so, for a huge number of sequenced fungal gene clusters predicted to code for biosynthetic activities, no corresponding metabolite has been identified so far. A better understanding of the chromatin-based regulatory network Appl Microbiol Biotechnol (2012) 95:1389–1404 will certainly contribute to the discovery of novel fungal metabolites. Acknowledgements The work from the author's laboratory de- scribed in this review was funded by Austrian Science Fund (FWF) Special Research Area Project S-10003-B17 and by the Vienna Sci- ence and Technology Fund (WWTF) project LS 09-042. 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