1394 group subsequently showed that LaeA only indirectly influ- ences the acetylation status of histone H3 (Reyes-Dominguez et al. 2010). This influence is based on competitiveness of “labeling” the crucial lysine (K9) in histone H3, which is acetylated together with H3K14 during gene activation, but which is trimethylated at K9 in the repressed state. Trimethy- lation of H3 at K9 in turn provides a docking site for the “reader” heterochromatin protein 1 (HepA in A. nidulans, hpo in N. crassa) and this binding event leads to the formation of heterochromatic structures at this locus. Interestingly, deletion of HepA or the H3K9 methyltransferase ClrD leads to permanently open chromatin at the ST locus and, similar to deacetylase inactivation, to partial reme- diation of ST gene expression in the absence of LaeA. Strikingly, loss of LaeA function showed strongly elevated H3K9 methylation levels suggesting that LaeA counteracts H3K9 trimethylation and thus heterochromatin formation at the ST locus. Reduction of H3K9me3 and HepA binding was also observed inside the newly identified monodictyphenon (MDP) cluster of A. nidulans as a consequence of the cclAΔ mutation (Bok et al. 2009). CclA is homologous to Bre2 in Saccharomyces cerevisiae, a protein that is part of the so- called COMPASS complex. This complex contains the SET1 methyltransferase that di- and trimethylates lysine 4 in histone H3 (H3K4me2/3). In a number of studies, this specific PTM was found to be associated with gene activation at euchromatic regions (Bernstein et al. 2005; Sims et al. 2007), but it has also been found as a mark required for subtelomeric gene silencing (Briggs et al. 2001; Mueller et al. 2006; Roguev et al. 2001). Most probably, in A. nidu- lans, the reduction of H3K9me3 at the MDP cluster in the cclAΔ strain is the consequence of a cross-talk between these two different PTMs of lysines in H3. But because the histone code is far more complex than has been tested here, we cannot say whether reduction of H3K4 methylation directly reduces H3K9 methylation (e.g., by blocking access of the ClrD H3K9 methyltransferase) or if this effect is mediated by some other, not tested, PTM at this locus. Whatever the molecular mechanism may be, it is remarkable that H3K9me3 reduction and thus the remov- al of heterochromatic marks is specific for genes lying inside the MDP cluster, whereas genes not belonging to the cluster show reduced H3K4 methylation but high H3K9me3 heterochromatic marks. Cluster-specific PTMs have also been observed for the ST pathway. Reduction of H3K9me3 during the switch from primary to second- ary metabolism was only seen in genes inside the ST cluster whereas genes lying immediately outside this biosynthetic region did not exhibit changes in their H3K9 methylation marks. How the borders between the heterochromatic and euchromatic domains are established and maintained still await clarification. Appl Microbiol Biotechnol (2012) 95:1389–1404 SM cluster regulation by facultative heterochromatin The two reports mentioned above (Bok et al. 2009; Reyes- Dominguez et al. 2010) were the first formal demonstrations that repression of SM gene expression during the active growth phase and primary metabolism employs the hetero- chromatin regulator HepA (HP1-homologue) bound to trime- thylated histone H3K9. Because repressive heterochromatin marks were dynamic and dropped after initiation of secondary metabolism and ST gene transcription the ST region was considered “facultatively heterochromatic”. In contrast to con- stitutive heterochromatin which is formed at centromeric and telomeric regions and which does not undergo de- condensation, facultative heterochromatin is reversible and can switch to euchromatic structures. Although bona fide constitutive heterochromatin has not been studied in Asper- gilli, there is a solid body of evidence for the existence of such structures in fungi such as Schizosaccharomyces pombe (Ekwall et al. 1995; Lejeune et al. 2010), and Neurospora crassa (Honda and Selker 2008; Honda et al. 2010; Honda et al. 2012; Lewis et al. 2010; Smith et al. 2008). However, during the heterochromatin–euchromatin switch silencing marks are replaced by activating marks, and this leads to the activation of genes in a specified genomic region (Brown 1966; Grewal and Jia 2007; Heitz 1928; Huisinga et al. 2006). Transcriptional silencing of genes by facultative het- erochromatin formation is thought to be more tight than simple transcriptional repression in euchromatin because dense chro- matin packaging represents a more restrictive and permanent barrier to the transcriptional machinery than repressor binding (Sun et al. 2001). Moreover, using chromatin condensation mechanisms, repressive structures can be more easily estab- lished over larger genomic regions. Because of these features, regulation by facultative heterochromatin is frequently found for developmentally regulated genes in higher eukaryotes (Fire et al. 1998; Kennerdell and Carthew 1998; Paddison and Hannon 2002). If developmental genes in fungi are associated with these chromatin structures is not known although muta- tions in the catalytic or regulatory subunits of the A. nidulans Saga/Ada complex (GcnE or AdaB) lead to a severe reduction of conidiation (Reyes-Dominguez et al. 2008) suggesting that histone marks and chromatin structure plays a central role at least in the asexual development of this fungus. As a consequence of chromatin-level regulation, signaling pathways for SM activation must communicate with the chro- matin modification machinery and implement this further up in the hierarchy level of regulation. The effects of HDAC inactivation and the detection of heterochromatic structures in the ST and MDP clusters provide an attractive hypothesis to explain co-regulation of large genomic regions and transcrip- tional silencing of SM biosynthetic genes during primary metabolism. In this model, secondary metabolic conditions would trigger the reversal of heterochromatic marks and the