naturally meet environmental triggers such as
stressors or nutrient limitations, the analysis of
secondary metabolism is difficult. The rapidly
growing number of genome studies has shown
that there are many more secondary metabolite
clusters in the genome of fungi than metabolites have been identified so far (Andersen et al.
2013; Inglis et al. 2013; van der Lee and Medema
2016). In order to eliminate this discrepancy
and exploit the full potential of fungal metabolite production, strategies have been developed
to activate silenced gene clusters and thus
enable their analysis in the laboratory (Gerke
and Braus 2014; Ren et al. 2017).
The easiest way to induce secondary metabolite production is to change the growth parameters as described by the OSMAC (one strain
many compounds) approach (Bode et al. 2002).
Parameters such as temperature, media components, pH, air supply, and light can be varied to
force the fungus to adapt its secondary metabolite repertoire. Since secondary metabolites
are often used in nature for communication,
competition, and defense, their production
can also be stimulated by co-cultivation with
other microorganisms (Netzker et al. 2015).
Additionally, genes involved in the metabolite
biosynthesis can be heterologously introduced
and expressed in suitable hosts. Heterologous
expression systems for fungal biosynthetic
genes have been designed, e.g., for A. niger
(Gressler et al. 2015), A. nidulans (Chiang
et al. 2013), or A. oryzae (Sakai et al. 2012).
Silenced biosynthetic gene clusters can also be
awakened by manipulating the transcriptional
machinery, the epigenetic status, or the degradation machinery of the cell.
In this chapter we focus on the molecular
regulatory links of the coordinated and specific
formation of secondary metabolites in different
phases of fungal developmental programs, with
a particular focus on the mold Aspergillus nidulans. This includes the control and interaction
of different genetic networks, which can be
organized chronologically and hierarchically
and can contain several feedback functions.
Genetic transcriptional control is linked to
post-translational histone modifications as epigenetic control and specific signal transduction
pathways. Several additional post-translational
control mechanisms, such as the attachment
and removal of ubiquitin, link fungal differentiation to the corresponding secondary metabolism by altering protein function and cellular
localization and by controlling protein stability
through the ubiquitin 26S proteasome as well as
autophagy degradation pathways.
II. Transcriptional Networks Linked
to Signal Transduction Pathways
Control Development and
Secondary Metabolism
Fungal growth and differentiation and the concomitant secondary metabolism occur in
response to internal and external signals that
are sensed through receptors and transported
by highly controlled signal transduction pathways. This leads to a choreography of changes
in transcription, translation, post-translational
histone modifications and protein stability followed by proteomic changes. Several examples
of well-studied signal transduction pathways
and responding transcriptional regulatory circuits are summarized in the following section.
A. Transcriptional Networks Interact in
Fungal Morphogenic Transitions
Transcriptional reprogramming plays a crucial
role in the morphological transition from vegetative fungal growth to developmental programs. Besides chromatin modifications (see
Sect. III), changes in transcriptomes are
mediated by approximately 80 families of currently classified fungal DNA binding transcription factors including a few examples of dual
factors with two distinct DNA binding
domains. Ascomycetous transcription factors
of the largest group carry a Zn 2 Cys 6 zinc cluster
domain. This domain is generally found in all
fungi but also in a few additional non-fungal
organisms. In contrast, four types of transcription factors carrying an APSES-type DNA binding domain (named after fungal developmental
transcription factors Asm1, Phd1, Sok2, Efg1,
and StuA), mating-type MAT a1, copper fist
178
J. Gerke et al.
stressors or nutrient limitations, the analysis of
secondary metabolism is difficult. The rapidly
growing number of genome studies has shown
that there are many more secondary metabolite
clusters in the genome of fungi than metabolites have been identified so far (Andersen et al.
2013; Inglis et al. 2013; van der Lee and Medema
2016). In order to eliminate this discrepancy
and exploit the full potential of fungal metabolite production, strategies have been developed
to activate silenced gene clusters and thus
enable their analysis in the laboratory (Gerke
and Braus 2014; Ren et al. 2017).
The easiest way to induce secondary metabolite production is to change the growth parameters as described by the OSMAC (one strain
many compounds) approach (Bode et al. 2002).
Parameters such as temperature, media components, pH, air supply, and light can be varied to
force the fungus to adapt its secondary metabolite repertoire. Since secondary metabolites
are often used in nature for communication,
competition, and defense, their production
can also be stimulated by co-cultivation with
other microorganisms (Netzker et al. 2015).
Additionally, genes involved in the metabolite
biosynthesis can be heterologously introduced
and expressed in suitable hosts. Heterologous
expression systems for fungal biosynthetic
genes have been designed, e.g., for A. niger
(Gressler et al. 2015), A. nidulans (Chiang
et al. 2013), or A. oryzae (Sakai et al. 2012).
Silenced biosynthetic gene clusters can also be
awakened by manipulating the transcriptional
machinery, the epigenetic status, or the degradation machinery of the cell.
In this chapter we focus on the molecular
regulatory links of the coordinated and specific
formation of secondary metabolites in different
phases of fungal developmental programs, with
a particular focus on the mold Aspergillus nidulans. This includes the control and interaction
of different genetic networks, which can be
organized chronologically and hierarchically
and can contain several feedback functions.
Genetic transcriptional control is linked to
post-translational histone modifications as epigenetic control and specific signal transduction
pathways. Several additional post-translational
control mechanisms, such as the attachment
and removal of ubiquitin, link fungal differentiation to the corresponding secondary metabolism by altering protein function and cellular
localization and by controlling protein stability
through the ubiquitin 26S proteasome as well as
autophagy degradation pathways.
II. Transcriptional Networks Linked
to Signal Transduction Pathways
Control Development and
Secondary Metabolism
Fungal growth and differentiation and the concomitant secondary metabolism occur in
response to internal and external signals that
are sensed through receptors and transported
by highly controlled signal transduction pathways. This leads to a choreography of changes
in transcription, translation, post-translational
histone modifications and protein stability followed by proteomic changes. Several examples
of well-studied signal transduction pathways
and responding transcriptional regulatory circuits are summarized in the following section.
A. Transcriptional Networks Interact in
Fungal Morphogenic Transitions
Transcriptional reprogramming plays a crucial
role in the morphological transition from vegetative fungal growth to developmental programs. Besides chromatin modifications (see
Sect. III), changes in transcriptomes are
mediated by approximately 80 families of currently classified fungal DNA binding transcription factors including a few examples of dual
factors with two distinct DNA binding
domains. Ascomycetous transcription factors
of the largest group carry a Zn 2 Cys 6 zinc cluster
domain. This domain is generally found in all
fungi but also in a few additional non-fungal
organisms. In contrast, four types of transcription factors carrying an APSES-type DNA binding domain (named after fungal developmental
transcription factors Asm1, Phd1, Sok2, Efg1,
and StuA), mating-type MAT a1, copper fist
178
J. Gerke et al.