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A systems biology approach to dissect the morphogenetic network of Aspergillus niger that links growth with product formation

Subject Area Biological Process Engineering
Term from 2020 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 431657715
 
Final Report Year 2025

Final Report Abstract

Filamentous fungi such as Aspergillus niger are used in biotechnology to transform renewable biomass into food, medicines and other platform chemicals. During submerged fermentation, heterogenous mixes of different mycelial growth types, such as pellets or dispersed mycelia, are formed. Previous data had suggested that macromorphology was crucial for the productivity of fermentation processes. However, very little was known about the genetic, (sub-)cellular, or mycelial biology which underpins macromorphological formation. Moreover, quantitative statements about how fungal productivity connects with macromorphology were lacking. The overall aim of this study was thus to develop rational genetic approaches to predict and engineer the macroscopic morphology of A. niger during fermentation, and to quantify how macromorphology links to citric acid or protein production. The aim was to harness co-expression network data that predict 57 ‘morphogenes’ connected with the citric acid cycle and predicted to impact A. niger morphology. Through a collaboration between the Technische Universität Berlin and the Tianjin Institute of Biotechnology, we used network biology, genetics, metabolic analyses, microscopy, and mathematical modelling to generate an extensive morphogene conditional expression library (n = 45 strains) and subsequently use this as a tool to prove, for the first time: (i) A. niger pellet formation is dependent largely on strain fitness (i.e., robust growth) and not hyphal morphology; (ii) pellet parameters (e.g. size, shape) depend on a combination of strain fitness and hyphal branching; (iii) growth rates, pellet macromorphology, and culture heterogeneity are tightly interconnected, yet can be de-coupled by moderate expression of a putative protein kinase encoding gene pkh2; (iv) targeting genes encoding Golgi/secretory proteins drastically impact macromorphology (e.g., sec26, sec27, cog4), rarely elevate protein titres, but remarkably can be used to abrogate citric acid production (e.g., secG, geaB, ageB); (v) elevated expression of the gene pkaC can be used to almost double citric acid titres in commercially used A. niger isolates; (vi) optimal citric acid titres are dependent on a non-compacted ‘hairy’ pellet surface; (vii) pellets with a diameter around 2 mm are optimal for protein titres but also require weak hyphal cell walls. The genetic tools, data, and protocols developed during this study thus enable precise genetic control of A. niger macromorphology and thus open new genetic leads for fermentation optimizations.

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