2.2.1 Histone acetylation
Histone acetylation modifying enzymes regulate transcription process by
changing the status of histone acetylation in chromosomes(Riaz et al.,
2015). Histone deacetylases (HDACs) and histone acetyltransferases
(HATs) are necessary to maintain epigenetic regulation of gene
expression by histone acetylation. HATs catalyze the reversible
acetylation reaction at the ε-amino group of lysine residues. Chromatin
relaxation and increased transcriptional activity of genes is associated
with neutralization of the positive charge of lysine residues by histone
acetylation. Meanwhile, HDACs can remove acetyl groups silencing the
transcriptional activity of genes and leading to chromatin condensation(Figure2) (Wawruszak et al., 2021). HDACs are divided into four
main classes: Class I (HDACs 1, 2, 3,8), Class IIa (HDAC4, 5, 7, 9) and
Class IIb (HDAC6, 10), Class III (SIRT1-SIRT7), Class IV (HDAC11)
(Wawruszak et al., 2021). HDACs (Class I, II and III) share sequence
similarity and require Zn2+ for deacetylase activity.
However, SIRT1-7(class III), show no sequence resemblance to members of
the classical family and require NAD+ as the
cofactor(Gregoretti et al., 2004; Whittle et al., 2007). In the HDAC
family, classes I and II are most associated with epilepsy, and have
been found to have the highest expression in the brain(Younus and Reddy,
2017). In the CNS, HDAC2 is thought to inhibit memory consolidation and
synaptic plasticity by inhibiting HDAC acetylation and HDAC5 is also
critical to memory formation(Younus and Reddy, 2017). HDAC6 plays a
neuroprotective role by promoting autophagy of damaged proteins(Boyault
et al., 2007). However, HDAC6 is also involved in regulating the
function of microtubule networks and impairs neuronal axon
transport(d’Ydewalle et al., 2012). In addition, the biological
functions of HDACs are also involved in metabolism, protein degradation,
angiogenesis, DNA damage, immune regulation, cell cycle and apoptosis.
In patients and animal models of epilepsy, changes of histone
acetylation have attracted widespread attention and have been considered
to be involved in epileptogenesis(Hauser et al., 2018; Boison and Rho,
2020). Relevant studies have shown that seizures promote deacetylation
of histone H4 of GluR2, which is closely related to epileptogenesis and
increased neuronal excitability(Huang et al., 2002; Tsankova et al.,
2004; Chen et al., 2021b). In a model of Tuberous Sclerosis Complex
(TSC) of mouse, histone H3 acetylation (H3K9Ac and H3K27Ac) levels are
generally decreased in the hippocampal neurons. Inhibition of HDAC
activity can restore histone H3 acetylation levels and improve abnormal
synaptic plasticity and seizure threshold in TSC2, which suggesting HDAC
inhibitors may be novel therapeutic strategies for TSC(Basu et al.,
2019). Multiple studies reported increased H3 phosphorylation in
pilocarpine and KA-induced seizures, which is believed to promote the
underlying mechanism that induces histone acetylation(Younus and Reddy,
2017). Furthermore, increased histone H4 acetylation is also reported in
pilocarpine, KA and electroconvulsive-induced epilepsy models(Huang et
al., 2002; Tsankova et al., 2004; Sng et al., 2006). Altered histone
acetylation at GluR2 and BDNF genes is an early event
triggered by SE. Meanwhile, increased histone H4 acetylation is also
linked to upregulated BDNF and c-FOS/c-JUN genes(Huang et al., 2002).
Related studies have shown that the downregulation of c-FOS
transcription may be achieved by histone H4 acetylation, while the
upregulation of BDNF transcription may be related to the regulation of
histone H3 acetylation(Tsankova et al., 2004).
Currently, several HDACs are upregulated during epilepsy. In the brain
tissue of patients with DR-TLE, HDAC2 is upregulated, which is
associated with reduced histone acetylation and gene expression. HDAC4
downregulates the gene expression of GABAA α1 subunit
and AMPAR subunit GluA2, which suggesting that decreased
GABAA α1 subunit and downregulated AMPAR subunit GluA2
are associated with histone deacetylation after
seizures(Fonseca-Barriendos et al., 2021). In addition, mutations in the
factor-induced-gene 4 (FIG4) gene are associated with multiple disorders
including epilepsy. Defects of HDAC1 may also explain FIG4-associated
disorders including epilepsy(Muraoka et al., 2021). Moreover, the
transformation/transcription domain-associated protein (TRRAP) is a
common component of many HAT complexes(Leduc et al., 2014). Some results
demonstrate TRRAP-dependent histone acetylation plays an essential role
in regulating neurogenesis and cell cycle(Tapias et al., 2014).
Meanwhile, it has been found that mutations of TRRAP can also cause
human neuropathies including epilepsy. In addition, TRRAP regulates
microtubule dynamics through the SP1 signaling pathway to prevent
neurodegeneration(Tapias et al., 2021).
In epilepsy, some drugs, including ADEs, also regulate histone
acetylation. Blocking HDACs with specific inhibitors appears to be an
effective therapeutic strategy for enhancing neuroprotection and
interfering with epileptogenesis(Boison and Rho, 2020). Ketogenic diet
(KD), as an important treatment for epilepsy, can enhance the production
of β-hydroxybutyrate which is a HDAC inhibitor(Lusardi et al., 2015;
Longo et al., 2019). Traumatic brain injury (TBI) is an important cause
of epileptogenesis. Related study has found that inhibition of HDAC can
improve learning and memory after TBI by combining with behavioral
therapy (Dash et al., 2009). Meanwhile, HDAC inhibitor ITF2357 has
neuroprotective effects and promotes neurological function recovery
following TBI(Shein et al., 2009). In addition, HDAC inhibitor can also
promote histone H3 acetylation and inhibt inflammatory response of
microglia following TBI in rats(Zhang et al., 2008). Valproic acid
(VPA), the most common AED, is known to suppress seizures by increasing
levels of GABA in the brain. Meanwhile, VPA is also a well-known HDAC
inhibitor(Lunke et al., 2021; Wawruszak et al., 2021). VPA regulates
histone acetylation together with HATs, suggesting that epigenetic
regulation of genes by VPA may be involved in the occurrence of
neurological diseases(Hu et al., 2020b). Relevant study has shown that
VPA may also participates in epileptogenesis by regulating HDACs(Hu et
al., 2020b). The study has found that the inhibitory concentration of
VPA on HDACs activity is about 0.3-1.0mM, which is within the
therapeutic range of VPA in human epilepsy(Blaauboer et al., 2022). Both
class I and class II HDACs are inhibited by VPA, with the highest
potency for class I HDACs, especially HDAC1(Phiel et al., 2001;
Blaauboer et al., 2022). The epigenetic effects of VPA mainly depend on
inhibition of HDACs and regulation of BDNF(Ghiglieri et al., 2010). VPA
and Other HDAC inhibitors can downregulate TrkB expression and BDNF/TrkB
signaling(Dedoni et al., 2019). Meanwhile, VPA is also involved in
inflammatory response by inhibiting of HDACs. VPA can mitigate traumatic
spinal cord injury-induced inflammation response by HDAC3-dependent
STAT1 and NF-κB pathway(Chen et al., 2018). In addition, sodium
butyrate, a critical HDAC inhibitor in the aliphatic fatty acid family,
can increase histones H3 and H4 acetylation in the hippocampus and
cerebral cortex of mice(Younus and Reddy, 2017). Sodium butyrate can
also improve the anticonvulsant activity of MK-801 (dizocilpine), an
NMDAR antagonist(Deutsch et al., 2008). Sodium butyrate has been shown
to modulate the effects of AED flurazepam to antagonize electrically
precipitated seizures(Deutsch et al., 2009). Meanwhile, sodium butyrate
significantly delays epileptogenesis, delays the development of seizures
and reduces the severity of behavioral seizures in mice(Younus and
Reddy, 2017). In the hippocampus kindling model of TLE, sodium butyrate
significantly inhibited HDAC activity and retarded the development of
limbic epileptogenesis. Meanwhile, inhibition of HDAC can significantly
reduce persistent seizures, eliminate the epileptic state, and
significantly reduce the sprouting mossy fiber(Reddy et al., 2018).
Histone H3 and H4 acetylation levels are decreased in epileptic rats,
while histone acetylation levels is significantly increased when treated
with sodium butyrate or VPA alone in the brain, especially combined
administration(Citraro et al., 2020). These findings suggest that sodium
butyrate has a strong antiepileptic effect by regulating HDACs.
In a word, these findings support the underlying theory that HDAC
inhibitors prevent epilepsy by interfering with epigenetic gene
expression profiles. Importantly, histone acetylation modifications may
have a crucial role in epileptogenesis and early treatment with HDAC
inhibitors might be a possible strategy for preventing epileptogenesis.