di-, and trimethylate this residue (Wagner and
Carpenter 2012). Methylation of H3K36 controls
N. crassa development as well as vegetative
growth, fungal virulence, and secondary metabolism of F. verticillioides (Adhvaryu et al. 2005;
Gu et al. 2017). Ash1 (asymmetric synthesis of
HO 1) represents a second histone methyltransferase for H3K36 in N. crassa or F. fujikuroi. N.
crassa methyl tags deposited by Set2 mark
actively transcribed genes, whereas the H3K36
methylation by Ash1 occurs in inactive genes. F.
fujikuroi Ash1 is involved in developmental processes and secondary metabolism (Janevska
et al. 2018; Bicocca et al. 2018).
Repressive marks associated with gene
silencing and heterochromatic regions include
the trimethylation of H3K9 or H3K27, which
are enriched in silenced fungal secondary
metabolite gene clusters. The H3K27 mark is
not used in A. nidulans, but in F. graminearum,
where the methyltransferase Kmt6 is responsible for the establishment of the H3K27Me3 and
regulates production of many secondary metabolites as well as development (Connolly et al.
2013).
Lysine demethylation is performed by histone demethylases, such as KdmA (lysine (K)demethylase A) and KdmB of A. nidulans. Both
are erasers that remove methyl marks from
histone H3. KdmA demethylates H3K36Me3
and has a dual role in transcriptional regulation
as co-repressor of primary metabolism genes
and activator of secondary metabolite genes.
KdmB demethylates H3K4Me3 and promotes
transcriptional downregulation as prerequisite
for accurate induction of A. nidulans secondary
metabolism (Gacek-Matthews et al. 2015, 2016).
One of the first described Aspergillus proteins with a methyltransferase domain is LaeA,
a master regulator of secondary metabolism.
LaeA, which is part of the velvet complex
(see Sect. II.A.2), possesses automethylation
activity (Patananan et al. 2013). Additionally,
it counteracts H3K9Me3 marks in repressive
heterochromatin, activating many secondary
metabolite biosynthetic gene clusters (ReyesDominguez et al. 2010, Fig. 8.3). However, the
exact molecular mechanism of LaeA function is
yet unknown. There are nine additional A.
nidulans LaeA-like methyltransferases (LlmALlmG, LlmI, LlmJ) that share sequence similarity with LaeA. LlmF interacts with VeA in the
cytoplasm and reduces its nuclear import,
resulting in altered development and secondary
metabolism, whereas the interaction of VeA
with LaeA takes place in the nucleus (Palmer
et al. 2013b, Fig. 8.2). VeA interacts with at least
two additional methyltransferases in both cellular compartments, the VeA interacting protein C (VipC) and the VipC-associated protein
B (VapB). The nuclear heterodimeric methyltransferases VipC-VapB are, together with the
membrane tethering zinc finger domain protein
VapA (VipC associated protein A), part of a
novel type of epigenetic signal transduction
pathway (Sarikaya-Bayram et al. 2014,
Fig. 8.2). VapA can exclude VipC-VapB from
the nucleus by forming the membrane-bound
trimeric VapA-VipC-VapB complex. Release of
the VipC-VapB heterodimer from VapA is
induced by a yet elusive molecular trigger and
leads to its transport from the membrane to the
nucleus. VipC-VapB interaction with VeA in
the cytoplasm inhibits its nuclear accumulation, resulting in decreased sexual development
and corresponding secondary metabolism.
Without VeA interaction, VipC-VapB enters
the nucleus and activates the light-promoted
brlA master regulatory gene of conidiation
and thereby the asexual differentiation program, for instance, by decreasing heterochromatin through VapB, which was shown to
reduce H3K9Me3 marks (Sarikaya-Bayram
et al. 2014; Figs. 8.2 and 8.3).
B. Histone Acetylation and Deacetylation
Histone hyperacetylation at amino groups
of lysine residues is, in most cases, associated
with euchromatin, whereas deacetylation results
in heterochromatin formation (Fig. 8.3). Promoter spreading of histone H3 or H4 acetylation
results in higher transcription and production of
186
J. Gerke et al.
Carpenter 2012). Methylation of H3K36 controls
N. crassa development as well as vegetative
growth, fungal virulence, and secondary metabolism of F. verticillioides (Adhvaryu et al. 2005;
Gu et al. 2017). Ash1 (asymmetric synthesis of
HO 1) represents a second histone methyltransferase for H3K36 in N. crassa or F. fujikuroi. N.
crassa methyl tags deposited by Set2 mark
actively transcribed genes, whereas the H3K36
methylation by Ash1 occurs in inactive genes. F.
fujikuroi Ash1 is involved in developmental processes and secondary metabolism (Janevska
et al. 2018; Bicocca et al. 2018).
Repressive marks associated with gene
silencing and heterochromatic regions include
the trimethylation of H3K9 or H3K27, which
are enriched in silenced fungal secondary
metabolite gene clusters. The H3K27 mark is
not used in A. nidulans, but in F. graminearum,
where the methyltransferase Kmt6 is responsible for the establishment of the H3K27Me3 and
regulates production of many secondary metabolites as well as development (Connolly et al.
2013).
Lysine demethylation is performed by histone demethylases, such as KdmA (lysine (K)demethylase A) and KdmB of A. nidulans. Both
are erasers that remove methyl marks from
histone H3. KdmA demethylates H3K36Me3
and has a dual role in transcriptional regulation
as co-repressor of primary metabolism genes
and activator of secondary metabolite genes.
KdmB demethylates H3K4Me3 and promotes
transcriptional downregulation as prerequisite
for accurate induction of A. nidulans secondary
metabolism (Gacek-Matthews et al. 2015, 2016).
One of the first described Aspergillus proteins with a methyltransferase domain is LaeA,
a master regulator of secondary metabolism.
LaeA, which is part of the velvet complex
(see Sect. II.A.2), possesses automethylation
activity (Patananan et al. 2013). Additionally,
it counteracts H3K9Me3 marks in repressive
heterochromatin, activating many secondary
metabolite biosynthetic gene clusters (ReyesDominguez et al. 2010, Fig. 8.3). However, the
exact molecular mechanism of LaeA function is
yet unknown. There are nine additional A.
nidulans LaeA-like methyltransferases (LlmALlmG, LlmI, LlmJ) that share sequence similarity with LaeA. LlmF interacts with VeA in the
cytoplasm and reduces its nuclear import,
resulting in altered development and secondary
metabolism, whereas the interaction of VeA
with LaeA takes place in the nucleus (Palmer
et al. 2013b, Fig. 8.2). VeA interacts with at least
two additional methyltransferases in both cellular compartments, the VeA interacting protein C (VipC) and the VipC-associated protein
B (VapB). The nuclear heterodimeric methyltransferases VipC-VapB are, together with the
membrane tethering zinc finger domain protein
VapA (VipC associated protein A), part of a
novel type of epigenetic signal transduction
pathway (Sarikaya-Bayram et al. 2014,
Fig. 8.2). VapA can exclude VipC-VapB from
the nucleus by forming the membrane-bound
trimeric VapA-VipC-VapB complex. Release of
the VipC-VapB heterodimer from VapA is
induced by a yet elusive molecular trigger and
leads to its transport from the membrane to the
nucleus. VipC-VapB interaction with VeA in
the cytoplasm inhibits its nuclear accumulation, resulting in decreased sexual development
and corresponding secondary metabolism.
Without VeA interaction, VipC-VapB enters
the nucleus and activates the light-promoted
brlA master regulatory gene of conidiation
and thereby the asexual differentiation program, for instance, by decreasing heterochromatin through VapB, which was shown to
reduce H3K9Me3 marks (Sarikaya-Bayram
et al. 2014; Figs. 8.2 and 8.3).
B. Histone Acetylation and Deacetylation
Histone hyperacetylation at amino groups
of lysine residues is, in most cases, associated
with euchromatin, whereas deacetylation results
in heterochromatin formation (Fig. 8.3). Promoter spreading of histone H3 or H4 acetylation
results in higher transcription and production of
186
J. Gerke et al.