Cordyceps militaris is currently exploited for commercial production of specialty products as its biomass constituents are enriched in bioactive compounds, such as cordycepin. The rational process development is important for economically feasible production of high quality bioproducts. Light is an abiotic factor affecting the cultivation process of this entomopathogenic fungus, particularly in its carotenoid formation. To uncover the cell response to light exposure, this study aimed to systematically investigate the metabolic responses of C. militaris strain TBRC6039 using integrative genome-wide transcriptome and genome-scale metabolic network (GSMN)-driven analysis. The genome-wide transcriptome analysis showed 8747 expressed genes in the glucose and sucrose cultures grown under light-programming and dark conditions. Of them, 689 differentially expressed genes were significant in response to the light-programming exposure. Through integration with the GSMN-driven analysis using the improved network (iRT1467), the reporter metabolites, e.g., adenosine-5′-monophosphate (AMP) and 2-oxoglutarate, were identified when cultivated under the carotenoid-producing condition controlled by light-programming exposure, linking to up-regulations of the metabolic genes involved in glyoxalase system, as well as cordycepin and carotenoid biosynthesis. These results indicated that C. militaris had a metabolic control in acclimatization to light exposure through transcriptional co-regulation, which supported the cell growth and cordycepin production in addition to the accumulation of carotenoid as a photo-protective bio-pigment. This study provides a perspective in manipulating the metabolic fluxes towards the target metabolites through either genetic or physiological approaches.

Cordyceps militaris is an edible fungus that produces many beneficial compounds, including cordycepin and carotenoid. In many fungi, growth, development and secondary metabolite production are controlled by crosstalk between light-signaling pathways and other regulatory cascades. However, little is known about the gene regulation upon light exposure in C. militaris. This study aims to construct a gene regulatory network (GRN) that responds to light in C. militaris. First, a genome-scale GRN was built based on transcription factor (TF)-target gene interactions predicted from the Regulatory Sequence Analysis Tools (RSAT). Then, a light-responsive GRN was extracted by integrating the transcriptomic data onto the genome-scale GRN. The light-responsive network contains 2689 genes and 6837 interactions. From the network, five TFs, Snf21 (CCM_04586), an AT-hook DNA-binding motif TF (CCM_08536), a homeobox TF (CCM_07504), a forkhead box protein L2 (CCM_02646) and a heat shock factor Hsf1 (CCM_05142), were identified as key regulators that co-regulate a large group of growth and developmental genes. The identified regulatory network and expression profiles from our analysis suggested how light may induce the growth and development of C. militaris into a sexual cycle. The light-mediated regulation also couples fungal development with cordycepin and carotenoid production. This study leads to an enhanced understanding of the light-responsive regulation of growth, development and secondary metabolite production in the fungi.

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