2.2.1 Histone methylation
Histone
methylation, is a unique post-translational modification catalyzed by
histone methyltransferases (HMTs), which occurs mainly on lysine (K) and
arginine (R) residues. Key enzymes involved in histone methylation
include HMTs and histone lysine demethylase (KDMs)(Jin et al., 2022).
Lysine methylation occurs in mono-, di-, and tri-states, whereas
arginine methylation only occurs in monoand di-states. Histone H3
methylation occurs at lysine residues K4, K9, K27, K36, and K79 and
histone H4 methylation occurs at lysine residues K20(Jin et al., 2022).
Most studies have found that H3K9me2/me3, H3K27me2/me3 and H4K20me3
frequently occur on gene silenced heterochromatin(Vermeulen et al.,
2010). In general, methylation at H3K9, H3K27, and H4K20 is associated
with transcriptional inhibition, while methylation at H3K4, H3K36, and
H3K79 is associated with gene transcription(Hon et al., 2009).
Currently, there are two main families of histone demethylases,
including lysine-specific demethylases (LSDs) and Jumonji C (JmjC)
domain-containing lysine demethylases
(JmjC-KDMs)(Jin
et al., 2022). Related study has found that both LSD1 and LSD2 function
as corepressors marks on H3K4 through the demethylation of mono- or
di-methyl (Han et al., 2019). However, LSD1 may also be as a coactivator
of androgen receptors by the demethylation of H3K9me1/me2(Metzger et
al., 2005). In addition, the members of the JmjC-KDM family are mainly
responsible for the demethylation of H3K4, H3K9, H3K27, H3K36, H3K79 and
H4K20 through cosubstrate2-oxoglutarate, dioxygen and Fe (II) as
cofactors(Labbé et al., 2013; Jin et al., 2022).
In the diseases of CNS, an association between between the severity of
intellectual disability and the dysregulation in the KDM5C-H3K4me3
pathway has been reported in neurodevelopmental disorders (NDDs)(Poeta
et al., 2021). Meanwhile, KDM5C variants are resulted in
neuropsychiatric symptoms, such as epilepsy, delayed development of
language and intellectual disability(Wei et al., 2016). In addition, the
development of intellectual disability and Rett syndrome has also been
found to be associated with mutations of JMJC-KDM (Sáez et al., 2016).
Recent studies have shown that histone methylation is also involved in
the pathogenesis and treatment of epilepsy. Setdb1, as the member of the
H3K9 HMT family, is widely expressed in the developmental brain and is
related to the inhibition of chromatin remodeling by targeting histone
H3K9 residues(Jiang et al., 2010). The inhibition of Setdb1-mediated
histone methylation of GRIN2B is related to the decreasing of
GluN2B expression(Jiang et al., 2010). It has also been found that
SETD1B, as an important component of the HMT complex, is involved in
epigenetic regulation of chromatin structure and gene expression by
specifically methylating histone H3K4(Krzyzewska et al., 2019). However,
SETD1B variants are related to autism, intellectual disability and
epilepsy. Meanwhile, SETD1B variants also contribute to a number of
clinical phenotypes, including variable epileptic phenotypes, delayed
language and delayed global development(Hiraide et al., 2018; Weerts et
al., 2021). LSD1 is a commonly expressed histone H3K4 demethylase that
acts as a transcription corepressor together with CoREST and
HDAC1/2(Rusconi et al., 2015). In a mouse epilepsy model, LSD1/KDM1A can
regulate neuronal excitability by neural-specific alternative
splicing(Rusconi et al., 2015). In addition, specific deletion of
neuroLSD1 in mice showed hypoexcitable and reduced susceptibility to
epilepsy(Rusconi et al., 2015). Related research has found that H3K9me2
and its enzyme euchromatic histone-lysine-methyltransferase 2 (G9a)
affect transcriptional regulation of the potassium channel 10 (Kcnj10)
gene which encodes the Kir4.1 channel and are sensitive to epileptic
seizure activity in epileptic rats(Zhang et al., 2018c).
These findings suggest that the regulation of histone methylation may
provide new research directions for the pathogenesis and treatment of
epilepsy. However, the mechanism of histone methylation regulation in
epilepsy is not completely clear and needs to be further explored in the
future.
2.3 Noncoding RNAs (ncRNA)
NcRNAs which include small (microRNA) and long (lncRNA), play a crucial
role in regulating gene expression. Bioinformatics analysis have found
that abnormal methylation of lncRNAs and microRNAs are associated with
neurotrophic factor signaling pathway, MAPK signaling pathway, drug
metabolism and ion channel activity (Xiao et al., 2018). In addition,
aberrantly methylation of ncRNAs may be involved in development and
progression of TLE(Xiao et al., 2018). NcRNAs are highly selectively
targeting and may play an important role in epilepsy, but their role in
refractory epilepsy still needs to be explored further. Thus, we will
discuss microRNAs and lncRNAs.