| The ultimate goal of digital cell modeling is to establish a mathematical whole-cell model containing various complex life activities of cells.In this study,we attempted to digitally model Aspergillus niger by means of sub-modules,including enzyme-constrained metabolic model and transcriptional regulation model,to indicate the direction for the final establishment of the mathematical whole-cell model of A.niger.Genomic-scale metabolic model(GSMM)is a powerful tool for studying the metabolic characteristics of cells.The new method of integrating multi-omics data into GSMM shows an enhanced effect on the prediction.It not only improves the accuracy of phenotypic prediction,but also enhances the reliability of the model in simulating complex biochemical phenomena.In this study,based on the basic GSMM model of A.niger,an enzyme constraint GSMM model,eciJB 1325 was constructed through integration of large-scale enzyme kinetics and proteomic data.The results showed that enzyme constraints effectively improved the phenotypic prediction ability of the new model,and the potential of gene modification target identification is extended.In addition,it also significantly reduced the solution space of the model,the variability of metabolic reaction flux over 40.10%was significantly reduced.The new model also shows versatility in other aspects,such as estimating kcat values in large-scale and predicting the enzyme expression profile of A.niger under different growth conditions.This shows that it is very effective to introduce the abundance information of enzyme into GSMM model to improve the model performance.The enzyme-constrained model could be used as a powerful tool for integrating the protein data to predict the metabolic phenotype of A.niger.Transcriptional regulation and gene expression play a central role in cell function.Studies on integration of transcription with GSMM have been reported,which requires modeling the effects of transcriptional regulation and gene expression on the rate of metabolic response.However,this only reflects the relationship between transcription and reaction,and the regulation effect of transcription factors on genes is not considered.In this study,the analysis method of transcription regulation data in batch fermentation process of A.niger was established.This was the first attempt to model the transcription regulation network of A.niger.It was not only an important tool to explore the transcription mechanism of A.niger.,but also an important part in the establishment process of the mathematical whole-cell model of A.niger,which had important progressive significance.By the method,activity analysis of transcription factors can be performed,and the function of the transcription factors can be predicted by combining the function of target genes;in addition,a transcription directed network can be established according to the regulation logic of TF-TG to study the interaction relationship between the transcription factors and the target genes.In this study,two important loops of whole-cell mathematical model of A.niger were completed.In the foreseeable future,with the rapid development of measurement technology and the more accurate and rich quantitative data of A.niger protein omics,the enzyme-constrained model will show greater application at the system level.In addition,The model is convenient and effective for processing large amount of data of gene expression profiles,it belongs to the integration and utilization of biological big data at the present stage and has reference significance.In the future,with the deepening of research on A.niger,the digging of the mechanisms and interaction relationships of multiple vital activities such as transcription,translation,post-translation modification and metabolism,the modular model will be further improved and finally integrated into a standardized comprehensive model. |
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