## 3 Semi-Synthetic and Molecular Activation of Silent BGCs
### Epigenetic Mining  
Of course, while transcriptional control by regulatory proteins is key to unlocking the silent potential of BGCs, epigenetic control also needs to be addressed. Within the broad grouping of microorganisms, but particularly in the higher order organisms such as fungi, phosphorylation, acetylation, methylation, ubiquitination, ADP-ribosylation, and glycosylation are known to regulate gene expression [112]. Although this aspect of BGC control is relatively uncharacterized, there is evidence that modulating epigenetic control can enhance or activate production of natural products in fungal organisms [80]. Some early indication of the importance of global regulatory mechanisms came from the observation that the putative nuclear regulator LaeA controlled fungal secondary metabolite production [113]. Around the same time, the observation that published fungal genomes demonstrate a propensity for the positioning of many putative natural product BGCs in the distal regions of chromosomes was reported [114]. When we consider that these regions typically exist in a heterochromatin state, where gene expression requires epigenetic control, a role in the expression of silent gene clusters linked to natural product expression appeared likely.  
Such was the case with disruption of the _hdaA_ gene encoding an _A. nidulans_ histone deacetylase (HDAC) leading to the transcriptional activation of genes involved in the biosynthesis of sterigmatocystin and penicillin [114], while deletion of the _cc1A_ gene encoding one of the eight COMPASS complex proteins, led to the activation of at least two silent gene clusters involved in the biosynthesis of emodin and the related compounds, monodictyphenone, and F9775A/F9775B [59]. This is not surprising given the analogous relationship between DNA supercoiling and microbial pathogenesis, suggesting an intrinsic role within the regulation of cellular physiology [115]. Deletion of _sumO_ in _A. nidulans_ caused a dramatic increase in asperthecin and a decrease of austinol/dehydroaustinol and sterigmatocystin production [116], while culturing in the presence of DNA methyltransferase (DNMT) or HDAC inhibitors led to isolation of novel compounds from several fungal organisms [32]. This latter observation shows the potential use for small-molecule epigenetic modifiers for accessing silent natural product pathways and enhancing the native production of fungal secondary metabolites. Furthermore, the success of this approach, with the added benefit of bypassing complex molecular manipulations and multifactorial culture based approaches, highlights the potential application of epigenetics to natural product discovery. Indeed, the multitude of chromatin modifications which have been found to regulate expression of secondary metabolites [117], and its potentially hierarchical position relative to transcriptional control, highlights the importance of understanding and exploiting this phenomenon for activation of silent secondary metabolism.  
Epigenetics may also play a role in triggering the activation of silent fungal BGCs in response to co-cultivation with bacteria. As already discussed, contact with competing microbial organisms can elicit activation of secondary metabolite production, with interspecies and interkingdom communication receiving a lot of attention in the fields of ecology and microbial pathogenesis [75; 76]. _S. rapamycincinicus_ triggered modification of fungal histones, eliciting production of the archetypal polykteide orsellinic acid and its derivatives in _A. nidulans_, following co-cultivation [118]. Deletion analysis of 36 of 40 acetyltransferases, including histone acetyltransferases (HATs) of _A. nidulans_, implicated the Saga/Ada complex which was also shown to play a major role in induction of other BGCs, such as sterigmatocystin, terrequinone, and penicillin [118].