secondary metabolites of the aflatoxin family in
Aspergilli (Roze et al. 2007; Reyes-Dominguez
et al. 2010).
Histone acetylation is performed by type A
or type B histone acetyltransferases (HATs) as
writers. Cytoplasmic type B HATs acetylate
newly synthesized histones prior to their
assembly into nucleosomes, whereas nuclear
type A HATs acetylate nucleosomal histones.
A well-studied group of type A HATs are
the Gcn5-related N-acetyltransferases (GNAT).
They catalyze the transfer of acetyl groups to
lysine residues on the histones H2B, H3, or H4
from acetyl-CoA donors. Founding member of
the family is the yeast Gcn5 (general control
non-derepressed 5), a transcriptional cofactor
associating as HAT with several complexes (e.g.
SAGA: Spt-Ada-Gcn5-Acetyltransferase). The
A. nidulans SAGA complex acetylates the histone sites H3K9 and H3K14 and regulates the
biosynthesis of penicillin, sterigmatocystin, terrequinone, and orsellinic acid (Nu ¨tzmann et al.
2011). Gcn5 is important for the control of the
mycotoxin deoxynivalenol biosynthesis in
Fusarium graminearum (Kong et al. 2018).
Numerous homologs of S. cerevisiae Gcn5 in
filamentous fungi are involved in growth,
development, regulation of secondary metabolite production, and pathogenicity.
The MYST (MOZ, Ybf2, Sas2, and Tip60)
family represents another type A HAT group
with a characteristic zinc finger in the highly
conserved MYST domain, which acetylates
H2A, H3, and H4 lysine residues. EsaA (essential SAS2-related acetyltransferase A), a MYST
HAT of A. nidulans, is an activator of secondary metabolism by acetylating H4K12 in the
sterigmatocystin, penicillin, terrequinone, and
orsellinic acid gene clusters (Soukup et al.
2012). MYST3 of A. parasiticus is required for
aflatoxin production (Roze et al. 2011b).
Histone deacetylation in fungi is performed by erasers such as the classical histone
deacetylases (HDACs) of class I (Rpd3/Hos2type) or class II (HDA1-type), with a zinc ion in
their catalytic site, or by non-conventional class
III SIR2-type sirtuin HDACs, which require
NAD
+ as cofactor (Brosch et al. 2008).
Yeast Rpd3 (reduced potassium dependency factor 3) as name-giving class I HDAC
regulates transcription by RNA polymerases I
and II through chromatin silencing and controls mitosis, meiosis, aging, or macroautophagy (see Sect. V.B). The corresponding A.
nidulans RpdA deacetylates H3 and H4 and is
essential for growth and conidiation (Tribus
et al. 2010). Trichostatin A, an inhibitor of
classical HDACs such as RpdA, is a promising
anticancer drug (Bauer et al. 2016) and inhibits
appressorium formation and decreases pathogenicity of the rice blast fungus Magnaporthe
oryzae (Izawa et al. 2009). A. nidulans HosA
(corresponding to yeast Hos2 (Hda One similar
2)) is another class I HDAC, which deacetylates
H4 and represses orsellinic acid production but
has inducing effects on other secondary metabolites by overriding the regulatory effects of
other HDACs (Pidroni et al. 2018). The
corresponding A. oryzae protein (HdaD/Hos2)
is involved in the regulation of growth, asexual
development, stress response, and the biosynthesis of the industrially important chelator
agent kojic acid (Kawauchi and Iwashita 2014).
The class II Hda1-type HDACs include
HdaA of A. nidulans, which represses sterigmatocystin and penicillin gene clusters as well as
additional clusters located close to telomeres.
HdaA, which can be overridden by class I
HDAC HosA, is therefore an antagonist of the
positive secondary metabolite gene cluster regulator LaeA (see Sects. II.B.2 and III.A). Analysis of the corresponding proteins of Alternaria
alternata or Penicillium expansum further support HDAC-mediated repression of secondary
metabolism as conserved function in fungi. One
exception is the A. fumigatus gliotoxin cluster,
which is activated by HdaA. The protein is
additionally required for growth and germination but not for virulence in this fungus (Shwab
et al. 2007; Lee et al. 2009).
Class III SIR2-type sirtuins HDACs include
SirA, which deacetylates H4K16 in the promotor regions of the sterigmatocystin and penicillin gene clusters and controls together with the
sirtuin HstA (homolog of SIR Two A) the formation of these metabolites. Some secondary
metabolite genes are repressed, whereas others
are activated, which reflects the complex control of histone modifications (Shwab et al. 2007;
Shimizu et al. 2012; Itoh et al. 2017). This is
8 Coordination of Fungal Secondary Metabolism and Development
187
Aspergilli (Roze et al. 2007; Reyes-Dominguez
et al. 2010).
Histone acetylation is performed by type A
or type B histone acetyltransferases (HATs) as
writers. Cytoplasmic type B HATs acetylate
newly synthesized histones prior to their
assembly into nucleosomes, whereas nuclear
type A HATs acetylate nucleosomal histones.
A well-studied group of type A HATs are
the Gcn5-related N-acetyltransferases (GNAT).
They catalyze the transfer of acetyl groups to
lysine residues on the histones H2B, H3, or H4
from acetyl-CoA donors. Founding member of
the family is the yeast Gcn5 (general control
non-derepressed 5), a transcriptional cofactor
associating as HAT with several complexes (e.g.
SAGA: Spt-Ada-Gcn5-Acetyltransferase). The
A. nidulans SAGA complex acetylates the histone sites H3K9 and H3K14 and regulates the
biosynthesis of penicillin, sterigmatocystin, terrequinone, and orsellinic acid (Nu ¨tzmann et al.
2011). Gcn5 is important for the control of the
mycotoxin deoxynivalenol biosynthesis in
Fusarium graminearum (Kong et al. 2018).
Numerous homologs of S. cerevisiae Gcn5 in
filamentous fungi are involved in growth,
development, regulation of secondary metabolite production, and pathogenicity.
The MYST (MOZ, Ybf2, Sas2, and Tip60)
family represents another type A HAT group
with a characteristic zinc finger in the highly
conserved MYST domain, which acetylates
H2A, H3, and H4 lysine residues. EsaA (essential SAS2-related acetyltransferase A), a MYST
HAT of A. nidulans, is an activator of secondary metabolism by acetylating H4K12 in the
sterigmatocystin, penicillin, terrequinone, and
orsellinic acid gene clusters (Soukup et al.
2012). MYST3 of A. parasiticus is required for
aflatoxin production (Roze et al. 2011b).
Histone deacetylation in fungi is performed by erasers such as the classical histone
deacetylases (HDACs) of class I (Rpd3/Hos2type) or class II (HDA1-type), with a zinc ion in
their catalytic site, or by non-conventional class
III SIR2-type sirtuin HDACs, which require
NAD
+ as cofactor (Brosch et al. 2008).
Yeast Rpd3 (reduced potassium dependency factor 3) as name-giving class I HDAC
regulates transcription by RNA polymerases I
and II through chromatin silencing and controls mitosis, meiosis, aging, or macroautophagy (see Sect. V.B). The corresponding A.
nidulans RpdA deacetylates H3 and H4 and is
essential for growth and conidiation (Tribus
et al. 2010). Trichostatin A, an inhibitor of
classical HDACs such as RpdA, is a promising
anticancer drug (Bauer et al. 2016) and inhibits
appressorium formation and decreases pathogenicity of the rice blast fungus Magnaporthe
oryzae (Izawa et al. 2009). A. nidulans HosA
(corresponding to yeast Hos2 (Hda One similar
2)) is another class I HDAC, which deacetylates
H4 and represses orsellinic acid production but
has inducing effects on other secondary metabolites by overriding the regulatory effects of
other HDACs (Pidroni et al. 2018). The
corresponding A. oryzae protein (HdaD/Hos2)
is involved in the regulation of growth, asexual
development, stress response, and the biosynthesis of the industrially important chelator
agent kojic acid (Kawauchi and Iwashita 2014).
The class II Hda1-type HDACs include
HdaA of A. nidulans, which represses sterigmatocystin and penicillin gene clusters as well as
additional clusters located close to telomeres.
HdaA, which can be overridden by class I
HDAC HosA, is therefore an antagonist of the
positive secondary metabolite gene cluster regulator LaeA (see Sects. II.B.2 and III.A). Analysis of the corresponding proteins of Alternaria
alternata or Penicillium expansum further support HDAC-mediated repression of secondary
metabolism as conserved function in fungi. One
exception is the A. fumigatus gliotoxin cluster,
which is activated by HdaA. The protein is
additionally required for growth and germination but not for virulence in this fungus (Shwab
et al. 2007; Lee et al. 2009).
Class III SIR2-type sirtuins HDACs include
SirA, which deacetylates H4K16 in the promotor regions of the sterigmatocystin and penicillin gene clusters and controls together with the
sirtuin HstA (homolog of SIR Two A) the formation of these metabolites. Some secondary
metabolite genes are repressed, whereas others
are activated, which reflects the complex control of histone modifications (Shwab et al. 2007;
Shimizu et al. 2012; Itoh et al. 2017). This is
8 Coordination of Fungal Secondary Metabolism and Development
187