condensed and transcriptionally inactive form
that can either be constitutive and serve as
structural element of the chromosomal centroand telomeres or be facultative and switch to
transcriptionally active euchromatin. Covalent
modifications of DNA or histones determine
whether hetero- or euchromatin is formed.
DNA can be reversibly modified by methylation, whereas lysine residues of histones can
be methylated, acetylated, ubiquitinated, or
sumoylated, and serine residues can be phosphorylated (Kouzarides 2007). Writers and erasers, which attach and remove modifications,
modify chromatin in different possible combinations. This results in a histone code in a
certain genomic region, which is recognized
by readers. Readers induce the restructuring
of chromatin into the open euchromatin or
the closed heterochromatin form and by this
regulate fungal development and secondary
metabolism (Pfannenstiel et al. 2018; Keller
2018). In the following paragraphs, we will discuss some writers and erasers in more detail
with the focus on consequences of histone or
DNA modification on secondary metabolism
and development.
A. DNA and Histone Methylation and
Demethylation
Methylation of chromatin can occur at DNA
and histones. Cytosine modification of DNA is
conserved between plants, mammals, and the
fungus N. crassa, but has not been found in all
fungi. Histone methylations and demethylations at lysine and arginine residues are present
in plants, mammals, and fungi and important
for fungal development and the associated secondary metabolism (Liu et al. 2010a; Greer and
Shi 2012; Nie et al. 2018; Fig. 8.3). Arginines can
be mono- or dimethylated (symmetric or asymmetric) and are less well studied than lysine
modifications, which include mono-, di-, or
trimethylations. Protein arginine (R) methyltransferases (PRMTs) are divided into four
major classes according to the methylation pattern they provide (Bachand 2007; Stopa et al.
2015). Three of nine human PRMTs (PRMT1,
PRMT3, PRMT5) are conserved in yeast or filamentous fungi (Bachand 2007). The
corresponding A. nidulans proteins RmtA and
RmtC possess H4R3
4 specificity, whereas RmtB
can methylate the histones H4, H3, and H2A
in vitro and all three methylate additional nonhistone substrates that affect transcriptional
regulation (Lee and Stallcup 2009; Bauer et al.
2010). RmtA and RmtC can affect mycelial
growth, oxidative stress response, development, or secondary metabolism in different
Aspergilli, whereas the role and the non-histone
substrates of RmtB still remain unclear (Bauer
et al. 2010; Satterlee et al. 2016).
Lysine methylation usually occurs at histones 3 and 4. The methyltransferase Set1 (SET
domain-containing 1) is part of the eight subunit COMPASS (COMPlex ASsociated with
Set1) complex involved as writer in mono-, di, and trimethylation of histone H3K4 euchromatin marks in fungi and in humans. Whereas
dysfunction in humans has been linked to several types of human cancer (Meeks and Shilatifard 2017), the degree of H3K4 methylation in
fungi has important implications on development and secondary metabolism. Defects in
COMPASS subunits, which significantly reduce
H3K4Me3
5 euchromatin marks, change significantly the secondary metabolite production
profile in Aspergillus and Fusarium, and the
development of Aspergillus (Palmer et al.
2013a; Studt et al. 2017). COMPASS-dependent
methylation of H3K4 is connected to the methylation of H3K79 by the non-Set domaincontaining enzyme Dot1 (disruptor of telomeric silencing 1) and dependent on histone
H2B ubiquitination (Shilatifard 2012). Dot1 is
to date the only non-SET domain-containing
enzyme for histone H3K79 methylation and
controls, e.g., production of aflatoxin, conidiation, sclerotia formation, and pathogenicity of
A. flavus (Liang et al. 2017).
Another epigenetic mark commonly associated with “active” chromatin is the trimethylation
of
H3K36
performed
by
the
methyltransferase Set2, which is able to mono-,
4 H3R4 ¼ histone H4 modified at arginine residue 3 (R3).
5 H3K4Me3 ¼ histone H3 trimethylated (Me3) at lysine residue
4 (K4).
8 Coordination of Fungal Secondary Metabolism and Development
185
that can either be constitutive and serve as
structural element of the chromosomal centroand telomeres or be facultative and switch to
transcriptionally active euchromatin. Covalent
modifications of DNA or histones determine
whether hetero- or euchromatin is formed.
DNA can be reversibly modified by methylation, whereas lysine residues of histones can
be methylated, acetylated, ubiquitinated, or
sumoylated, and serine residues can be phosphorylated (Kouzarides 2007). Writers and erasers, which attach and remove modifications,
modify chromatin in different possible combinations. This results in a histone code in a
certain genomic region, which is recognized
by readers. Readers induce the restructuring
of chromatin into the open euchromatin or
the closed heterochromatin form and by this
regulate fungal development and secondary
metabolism (Pfannenstiel et al. 2018; Keller
2018). In the following paragraphs, we will discuss some writers and erasers in more detail
with the focus on consequences of histone or
DNA modification on secondary metabolism
and development.
A. DNA and Histone Methylation and
Demethylation
Methylation of chromatin can occur at DNA
and histones. Cytosine modification of DNA is
conserved between plants, mammals, and the
fungus N. crassa, but has not been found in all
fungi. Histone methylations and demethylations at lysine and arginine residues are present
in plants, mammals, and fungi and important
for fungal development and the associated secondary metabolism (Liu et al. 2010a; Greer and
Shi 2012; Nie et al. 2018; Fig. 8.3). Arginines can
be mono- or dimethylated (symmetric or asymmetric) and are less well studied than lysine
modifications, which include mono-, di-, or
trimethylations. Protein arginine (R) methyltransferases (PRMTs) are divided into four
major classes according to the methylation pattern they provide (Bachand 2007; Stopa et al.
2015). Three of nine human PRMTs (PRMT1,
PRMT3, PRMT5) are conserved in yeast or filamentous fungi (Bachand 2007). The
corresponding A. nidulans proteins RmtA and
RmtC possess H4R3
4 specificity, whereas RmtB
can methylate the histones H4, H3, and H2A
in vitro and all three methylate additional nonhistone substrates that affect transcriptional
regulation (Lee and Stallcup 2009; Bauer et al.
2010). RmtA and RmtC can affect mycelial
growth, oxidative stress response, development, or secondary metabolism in different
Aspergilli, whereas the role and the non-histone
substrates of RmtB still remain unclear (Bauer
et al. 2010; Satterlee et al. 2016).
Lysine methylation usually occurs at histones 3 and 4. The methyltransferase Set1 (SET
domain-containing 1) is part of the eight subunit COMPASS (COMPlex ASsociated with
Set1) complex involved as writer in mono-, di, and trimethylation of histone H3K4 euchromatin marks in fungi and in humans. Whereas
dysfunction in humans has been linked to several types of human cancer (Meeks and Shilatifard 2017), the degree of H3K4 methylation in
fungi has important implications on development and secondary metabolism. Defects in
COMPASS subunits, which significantly reduce
H3K4Me3
5 euchromatin marks, change significantly the secondary metabolite production
profile in Aspergillus and Fusarium, and the
development of Aspergillus (Palmer et al.
2013a; Studt et al. 2017). COMPASS-dependent
methylation of H3K4 is connected to the methylation of H3K79 by the non-Set domaincontaining enzyme Dot1 (disruptor of telomeric silencing 1) and dependent on histone
H2B ubiquitination (Shilatifard 2012). Dot1 is
to date the only non-SET domain-containing
enzyme for histone H3K79 methylation and
controls, e.g., production of aflatoxin, conidiation, sclerotia formation, and pathogenicity of
A. flavus (Liang et al. 2017).
Another epigenetic mark commonly associated with “active” chromatin is the trimethylation
of
H3K36
performed
by
the
methyltransferase Set2, which is able to mono-,
4 H3R4 ¼ histone H4 modified at arginine residue 3 (R3).
5 H3K4Me3 ¼ histone H3 trimethylated (Me3) at lysine residue
4 (K4).
8 Coordination of Fungal Secondary Metabolism and Development
185