Transcriptional memory drives accelerated re-activation of several biosynthetic gene clusters in Aspergillus nidulans

Organisms are repeatedly exposed to fluctuating environmental and nutritional conditions. Transcriptional memory has been shown to be a mechanism to cope with these fluctuations because it increases the speed and the magnitude of the cellular response to a certain re-occurring condition and therefore optimizes adaptation and fitness in a given environment. We found that genes coding for sterigmatocystin (ST) production in Aspergillus nidulans are activated stronger when cells are repeatedly exposed to nutrient starvation, compared to cells that experience this condition for the first time. We studied possible underlying mechanisms and found that persistence of the transcription factor AflR, which can undergo activation-inactivation cycles, accounts for a large part of the memory. In addition, a chromatin-based mechanism through histone H3 lysine 4 dimethylation (H3K4me2) and extracellular metabolites produced during the first activation phase contribute to the memory process. Genome-wide transcriptome and chromatin analyses showed that only a few genes within the ST and other starvation-induced biosynthetic gene clusters gain the H3K4me2 mark during the 1st activation, but the majority of those which receive the mark also maintain it during the subsequent repression and re-activation phase. Combined with previous findings on chromatin-level regulation of biosynthetic gene clusters (BGCs) our recent data suggest that the H3K4me2 mark may contribute to the correct 3D organization of BGCs and that this is a prerequisite for activation and transcriptional memory.