scholarly journals Beyond the biosynthetic gene cluster paradigm: Genome-wide co-expression networks connect clustered and unclustered transcription factors to secondary metabolic pathways

2020 ◽  
Author(s):  
Min Jin Kwon ◽  
Charlotte Steiniger ◽  
Timothy C. Cairns ◽  
Jennifer H. Wisecaver ◽  
Abigail Lind ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Aspergillus Niger ◽  
Secondary Metabolites ◽  
Metabolic Pathways ◽  
Correlation Coefficients ◽  
Genetic Networks ◽  
Cell Factory ◽  
Biosynthetic Gene ◽  
Genome Wide ◽  
Novel Drug

AbstractFungal secondary metabolites are widely used as therapeutics and are vital components of drug discovery programs. A major challenge hindering discovery of novel secondary metabolites is that the underlying pathways involved in their biosynthesis are transcriptionally silent in typical laboratory growth conditions, making it difficult to identify the transcriptional networks that they are embedded in. Furthermore, while the genes participating in secondary metabolic pathways are typically found in contiguous clusters on the genome, known as biosynthetic gene clusters (BGCs), this is not always the case, especially for global and pathway-specific regulators of pathways’ activities. To address these challenges, we used 283 genome-wide gene expression datasets of the ascomycete cell factory Aspergillus niger generated during growth under 155 different conditions to construct two gene co-expression networks based on Spearman’s correlation coefficients (SCC) and on mutual rank-transformed Pearson’s correlation coefficients (MR-PCC). By mining these networks, we predicted six transcription factors named MjkA – MjkF to concomitantly regulate secondary metabolism in A. niger. Over-expression of each transcription factor using the Tet-on cassette modulated production of multiple secondary metabolites. We found that the SCC and MR-PCC approaches complemented each other, enabling the delineation of global (SCC) and pathway-specific (MR-PCC) transcription factors, respectively. These results highlight the great potential of co-expression network approaches to identify and activate fungal secondary metabolic pathways and their products. More broadly, we argue that novel drug discovery programs in fungi should move beyond the BGC paradigm and focus on understanding the global regulatory networks in which secondary metabolic pathways are embedded.ImportanceThere is an urgent need for novel bioactive molecules in both agriculture and medicine. The genomes of fungi are thought to contain vast numbers of metabolic pathways involved in the biosynthesis of secondary metabolites with diverse bioactivities. Because these metabolites are biosynthesized only under specific conditions, the vast majority of fungal pharmacopeia awaits discovery. To discover the genetic networks that regulate the activity of secondary metabolites, we examined the genome-wide profiles of gene activity of the cell factory Aspergillus niger across hundreds of conditions. By constructing global networks that link genes with similar activities across conditions, we identified six global and pathway-specific regulators of secondary metabolite biosynthesis. Our study shows that elucidating the behavior of the genetic networks of fungi under diverse conditions harbors enormous promise for understanding fungal secondary metabolism, which ultimately may lead to novel drug candidates.

scholarly journals Beyond the Biosynthetic Gene Cluster Paradigm: Genome-Wide Coexpression Networks Connect Clustered and Unclustered Transcription Factors to Secondary Metabolic Pathways

2021 ◽  
Author(s):  
Min Jin Kwon ◽  
Charlotte Steiniger ◽  
Timothy C. Cairns ◽  
Jennifer H. Wisecaver ◽  
Abigail L. Lind ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Secondary Metabolites ◽  
Gene Cluster ◽  
Metabolic Pathways ◽  
Biosynthetic Gene Cluster ◽  
Bioactive Molecules ◽  
Biosynthetic Gene ◽  
Genome Wide ◽  
Coexpression Networks

There is an urgent need for novel bioactive molecules in both agriculture and medicine. The genomes of fungi are thought to contain vast numbers of metabolic pathways involved in the biosynthesis of secondary metabolites with diverse bioactivities.

scholarly journals Something old, something new: challenges and developments in Aspergillus niger biotechnology

2021 ◽  
Author(s):  
Timothy C. Cairns ◽  
Lars Barthel ◽  
Vera Meyer
Keyword(s):  
Aspergillus Niger ◽  
Secondary Metabolites ◽  
Organic Acids ◽  
Industrial Applications ◽  
Cell Factory ◽  
Special Focus ◽  
Product Portfolio ◽  
Filamentous Ascomycete ◽  
Technological Advances ◽  
Technological Developments

Abstract The filamentous ascomycete fungus Aspergillus niger is a prolific secretor of organic acids, proteins, enzymes and secondary metabolites. Throughout the last century, biotechnologists have developed A. niger into a multipurpose cell factory with a product portfolio worth billions of dollars each year. Recent technological advances, from genome editing to other molecular and omics tools, promise to revolutionize our understanding of A. niger biology, ultimately to increase efficiency of existing industrial applications or even to make entirely new products. However, various challenges to this biotechnological vision, many several decades old, still limit applications of this fungus. These include an inability to tightly control A. niger growth for optimal productivity, and a lack of high-throughput cultivation conditions for mutant screening. In this mini-review, we summarize the current state-of-the-art for A. niger biotechnology with special focus on organic acids (citric acid, malic acid, gluconic acid and itaconic acid), secreted proteins and secondary metabolites, and discuss how new technological developments can be applied to comprehensively address a variety of old and persistent challenges.

scholarly journals Biosynthetic gene clusters, secondary metabolite profiles, and cards of virulence in the closest nonpathogenic relatives of Aspergillus fumigatus

2020 ◽  
Author(s):  
Jacob L. Steenwyk ◽  
Matthew E. Mead ◽  
Sonja L. Knowles ◽  
Huzefa A. Raja ◽  
Christopher D. Roberts ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Aspergillus Fumigatus ◽  
Secondary Metabolism ◽  
Human Disease ◽  
Metabolic Pathways ◽  
Fungal Pathogen ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Close Relatives

AbstractAspergillus fumigatus is a major human pathogen that causes hundreds of thousands of infections yearly with high mortality rates. In contrast, Aspergillus fischeri and the recently described Aspergillus oerlinghausenensis, the two species most closely related to A. fumigatus, are not known to be pathogenic. Some of the “cards of virulence” that A. fumigatus possesses are secondary metabolites that impair the host immune system, protect from host immune cell attacks, or acquire key nutrients. Secondary metabolites and the biosynthetic gene clusters (BGCs) that typically encode them often vary within and between fungal species. To gain insight into whether secondary metabolism-associated cards of virulence vary between A. fumigatus, A. oerlinghausenensis, and A. fischeri, we conducted extensive genomic and secondary metabolite profiling analyses. By analyzing multiple A. fumigatus, one A. oerlinghausenensis, and multiple A. fischeri strains, we identified both conserved and diverged secondary metabolism-associated cards of virulence. For example, we found that all species and strains examined biosynthesized the major virulence factor gliotoxin, consistent with the conservation of the gliotoxin BGC across genomes. However, species differed in their biosynthesis of fumagillin and pseurotin, both contributors to host tissue damage during invasive aspergillosis; these differences were reflected in sequence divergence of the intertwined fumagillin/pseurotin BGCs across genomes. These results delineate the similarities and differences in secondary metabolism-associated cards of virulence between a major fungal pathogen and its nonpathogenic closest relatives, shedding light into the genetic and phenotypic changes associated with the evolution of fungal pathogenicity.ImportanceThe major fungal pathogen Aspergillus fumigatus kills tens of thousands each year. In contrast, the two closest relatives of A. fumigatus, namely Aspergillus fischeri and Aspergillus oerlinghausenensis, are not considered pathogenic. A. fumigatus virulence stems, partly, from its ability to produce small molecules called secondary metabolites that have potent activities during infection. In this study, we examined whether A. fumigatus secondary metabolites and the metabolic pathways involved in their production are conserved in A. oerlinghausenensis and A. fischeri. We found that the nonpathogenic close relatives of A. fumigatus produce some, but not all, secondary metabolites thought to contribute to the success of A. fumigatus in causing human disease and that these similarities and differences were reflected in the underlying metabolic pathways involved in their biosynthesis. Compared to its nonpathogenic close relatives, A. fumigatus produces a distinct cocktail of secondary metabolites, which likely contributes to these organisms’ vastly different potentials to cause human disease. More broadly, the study of nonpathogenic organisms that have virulence-related traits, but are not currently considered agents of human disease, may facilitate the prediction of species capable of posing future threats to human health.

Transcriptional regulation of secondary metabolism

2003 ◽  
Vol 30 (9) ◽  
pp. 913 ◽  
Author(s):  
Kevin M. Davies ◽  
Kathy E. Schwinn
Keyword(s):  
Transcription Factor ◽  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Secondary Metabolites ◽  
Metabolic Pathways ◽  
Target Genes ◽  
Control Point ◽  
Indole Alkaloid ◽  
Phenylpropanoid Pathway ◽  
Genes Encoding

Plants produce secondary metabolites during development and in response to environmental stimuli such as light or pathogen attack. Transcriptional regulation provides the most important control point for the secondary metabolic pathways studied to date. In this article we review the data on the transcription factors that modulate this regulation. For the phenylpropanoid pathway, much is understood about both the specific sequences in the target genes (cis-elements) that are involved in responses to environmental and developmental stimuli, and the transcription factors involved. Most information is available for the light induction of the genes for hydroxycinnamic acid production, the production of anthocyanins in leaves and floral tissues, and the production of proanthocyanidins in seeds. Some of the functional interactions between the different types of transcription factor are now being elucidated, and upstream regulators of the genes encoding the transcription factors identified. For other secondary metabolic pathways much less is known, although good progress has been made on identifying transcription factors involved in controlling terpenoid indole alkaloid production. The identification of defined transcription factor genes provides tools for modulating both the amount and distribution of secondary metabolites in plants, and the validity of this approach has been well established by transgenic plants with modified flavonoid accumulation patterns.

scholarly journals In Silico Identification of MYB and bHLH Families Reveals Candidate Transcription Factors for Secondary Metabolic Pathways in Cannabis sativa L.

Plants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1540
Author(s):  
Laura Bassolino ◽  
Matteo Buti ◽  
Flavia Fulvio ◽  
Alessandro Pennesi ◽  
Giuseppe Mandolino ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Metabolic Pathways ◽  
Cannabis Sativa ◽  
Scale Up ◽  
Candidate Gene Approach ◽  
Main Role ◽  
Genome Wide ◽  
Comprehensive Knowledge ◽  
Genomic Studies ◽  
Comparative Phylogenetic Analysis

Plant secondary metabolic pathways are finely regulated by the activity of transcription factors, among which members of the bHLH and MYB subfamilies play a main role. Cannabis sativa L. is a unique officinal plant species with over 600 synthesized phytochemicals having diverse scale-up industrial and pharmaceutical usage. Despite comprehensive knowledge of cannabinoids’ metabolic pathways, very little is known about their regulation, while the literature on flavonoids’ metabolic pathways is still scarce. In this study, we provide the first genome-wide analysis of bHLH and MYB families in C. sativa reference cultivar CBDRx and identification of candidate coding sequences for these transcription factors. Cannabis sativa bHLHs and MYBs were then classified into functional subfamilies through comparative phylogenetic analysis with A. thaliana transcription factors. Analyses of gene structure and motif distribution confirmed that CsbHLHs and CsMYBs belonging to the same evolutionary clade share common features at both gene and amino acidic level. Candidate regulatory genes for key metabolic pathways leading to flavonoid and cannabinoid synthesis in Cannabis were also retrieved. Furthermore, a candidate gene approach was used to identify structural enzyme-coding genes for flavonoid and cannabinoid synthesis. Taken as a whole, this work represents a valuable resource of candidate genes for further investigation of the C. sativa cannabinoid and flavonoid metabolic pathways for genomic studies and breeding programs.

scholarly journals Global biogeographic sampling of bacterial secondary metabolism

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Zachary Charlop-Powers ◽  
Jeremy G Owen ◽  
Boojala Vijay B Reddy ◽  
Melinda A Ternei ◽  
Denise O Guimarães ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Genome Sequencing ◽  
Geographic Distance ◽  
Gene Clusters ◽  
Natural World ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Road Map ◽  
Two Factors ◽  
Natural Products Discovery

Recent bacterial (meta)genome sequencing efforts suggest the existence of an enormous untapped reservoir of natural-product-encoding biosynthetic gene clusters in the environment. Here we use the pyro-sequencing of PCR amplicons derived from both nonribosomal peptide adenylation domains and polyketide ketosynthase domains to compare biosynthetic diversity in soil microbiomes from around the globe. We see large differences in domain populations from all except the most proximal and biome-similar samples, suggesting that most microbiomes will encode largely distinct collections of bacterial secondary metabolites. Our data indicate a correlation between two factors, geographic distance and biome-type, and the biosynthetic diversity found in soil environments. By assigning reads to known gene clusters we identify hotspots of biomedically relevant biosynthetic diversity. These observations not only provide new insights into the natural world, they also provide a road map for guiding future natural products discovery efforts.

scholarly journals Dynamic histone acetylation in floral volatile synthesis and emission in petunia flowers

2021 ◽  
Author(s):  
Ryan M Patrick ◽  
Xing-Qi Huang ◽  
Natalia Dudareva ◽  
Ying Li
Keyword(s):  
Transcriptional Activation ◽  
Metabolic Pathways ◽  
Transcriptional Repression ◽  
Metabolic Networks ◽  
Underlying Mechanism ◽  
Expression Of Genes ◽  
Genome Wide ◽  
Chemical Inhibitors ◽  
Volatile Organic ◽  
Floral Volatile

Abstract Biosynthesis of secondary metabolites relies on primary metabolic pathways to provide precursors, energy, and cofactors, thus requiring coordinated regulation of primary and secondary metabolic networks. However, to date, it remains largely unknown how this coordination is achieved. Using Petunia hybrida flowers, which emit high levels of phenylpropanoid/benzenoid volatile organic compounds (VOCs), we uncovered genome-wide dynamic deposition of histone H3 lysine 9 acetylation (H3K9ac) during anthesis as an underlying mechanism to coordinate primary and secondary metabolic networks. The observed epigenome reprogramming is accompanied by transcriptional activation at gene loci involved in primary metabolic pathways that provide precursor phenylalanine, as well as secondary metabolic pathways to produce volatile compounds. We also observed transcriptional repression among genes involved in alternative phenylpropanoid branches that compete for metabolic precursors. We show that GNAT family histone acetyltransferase(s) (HATs) are required for the expression of genes involved in VOC biosynthesis and emission, by using chemical inhibitors of HATs, and by knocking down a specific HAT gene, ELP3, through transient RNAi. Together, our study supports that regulatory mechanisms at chromatin level may play an essential role in activating primary and secondary metabolic pathways to regulate VOC synthesis in petunia flowers.

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