4 HAT and Other Diseases
Altered or abnormal HAT activity is also related to several other diseases, including
cardiac hypertrophy, asthma, AIDS and neurodegenerative disorders. Well-studied
are the roles of different HATs in neural development. CBP/p300 are crucial
enzymes in development. Indeed, dysfunctions of CBP/p300 activity deregulate
gene transcriptions that are prominently linked to Rubinstein-Taybi syndrome, an
incurable genetic disorder with combination of mental retardation and physical
features. Most of Rubinstein-Taybi syndrome patients carry heterozygous mutation
in gene CBP, while only a small percentage of patients show mutations in p300 gene
[62]. Several studies in transgenic mice have described a role for CBP/p300 in neural
development [63]. Disruption of both p300 and CBP expression leads to embryonic
lethality in mice between embryonic day 9 (E9.0) and E11.5, associated with
different types of neural tube closure and embryonic vascular and cardiac defects.
Surprisingly, p300 +/À mice also manifested considerable embryonic lethality.
GCN5 expression and activity are also required for the corrected neural tube closure.
Notably, GCN5-null mice also exhibit early embryonic lethality [64], while deletion
of PCAF causes no obvious abnormal phenotypes in mice [65, 66]. Despite this, mice
deleted of both GCN5 and PCAF show a more severe phenotype than GCN5-null
mice, indicating that some PCAF functions are redundant to those of GCN5 in the
early stages of embryogenesis [66]. Interestingly, deficits in learning abilities, spatial
and recognition memory as well as in both short-term and contextual long-term
memory have been observed in adult PCAF null mice [67]. Little is known about
the role of MYST members in neural development. Heterozygous mutations of
MYST members exhibit no relevant phenotypes, while homozygous mutations of
main members (TIP60, HBO1 and MOF) result in early embryonic lethality
around the blastocyst stage or post-gastrulation. MORF is highly expressed in the
brain, and its mutations are associated with different neurodevelopmental disorders
in humans. In particular, mutations of MORF have been found in patients affected
by genitopatellar syndrome, a skeletal dysplasia with cerebral and genital
anomalies [68].
The role of HATs has been also extensively studied in heart disease. By using a
genetic approach, it has been found that HAT members are key factors in the
pathological processes of cardiac remodelling, including hypertrophy, contractility
and fibrosis [69]. p300/CBP family plays critical roles in physiological and pathological growth of cardiac myocytes. The role of p300 in normal cardiac transcription
is demonstrated by p300 null mice showing cardiac structural defects and reduced
expression of muscle structural proteins such as β-myosin heavy chain and α-actinin.
Moreover, p300/CBP activity is enhanced by signalling pathways that promote
cardiac hypertrophy, and ectopic overexpression of both enzymes stimulates cardiac
growth, while dominant-negative mutants of p300 block agonist-mediated cardiac
growth [70].
Lysine acetylation is also essential in regulating immuno-metabolism, and it has
been implicated as both a post-transcriptional and post-translational mechanism in
102
D. Trisciuoglio and D. Rotili
Altered or abnormal HAT activity is also related to several other diseases, including
cardiac hypertrophy, asthma, AIDS and neurodegenerative disorders. Well-studied
are the roles of different HATs in neural development. CBP/p300 are crucial
enzymes in development. Indeed, dysfunctions of CBP/p300 activity deregulate
gene transcriptions that are prominently linked to Rubinstein-Taybi syndrome, an
incurable genetic disorder with combination of mental retardation and physical
features. Most of Rubinstein-Taybi syndrome patients carry heterozygous mutation
in gene CBP, while only a small percentage of patients show mutations in p300 gene
[62]. Several studies in transgenic mice have described a role for CBP/p300 in neural
development [63]. Disruption of both p300 and CBP expression leads to embryonic
lethality in mice between embryonic day 9 (E9.0) and E11.5, associated with
different types of neural tube closure and embryonic vascular and cardiac defects.
Surprisingly, p300 +/À mice also manifested considerable embryonic lethality.
GCN5 expression and activity are also required for the corrected neural tube closure.
Notably, GCN5-null mice also exhibit early embryonic lethality [64], while deletion
of PCAF causes no obvious abnormal phenotypes in mice [65, 66]. Despite this, mice
deleted of both GCN5 and PCAF show a more severe phenotype than GCN5-null
mice, indicating that some PCAF functions are redundant to those of GCN5 in the
early stages of embryogenesis [66]. Interestingly, deficits in learning abilities, spatial
and recognition memory as well as in both short-term and contextual long-term
memory have been observed in adult PCAF null mice [67]. Little is known about
the role of MYST members in neural development. Heterozygous mutations of
MYST members exhibit no relevant phenotypes, while homozygous mutations of
main members (TIP60, HBO1 and MOF) result in early embryonic lethality
around the blastocyst stage or post-gastrulation. MORF is highly expressed in the
brain, and its mutations are associated with different neurodevelopmental disorders
in humans. In particular, mutations of MORF have been found in patients affected
by genitopatellar syndrome, a skeletal dysplasia with cerebral and genital
anomalies [68].
The role of HATs has been also extensively studied in heart disease. By using a
genetic approach, it has been found that HAT members are key factors in the
pathological processes of cardiac remodelling, including hypertrophy, contractility
and fibrosis [69]. p300/CBP family plays critical roles in physiological and pathological growth of cardiac myocytes. The role of p300 in normal cardiac transcription
is demonstrated by p300 null mice showing cardiac structural defects and reduced
expression of muscle structural proteins such as β-myosin heavy chain and α-actinin.
Moreover, p300/CBP activity is enhanced by signalling pathways that promote
cardiac hypertrophy, and ectopic overexpression of both enzymes stimulates cardiac
growth, while dominant-negative mutants of p300 block agonist-mediated cardiac
growth [70].
Lysine acetylation is also essential in regulating immuno-metabolism, and it has
been implicated as both a post-transcriptional and post-translational mechanism in
102
D. Trisciuoglio and D. Rotili