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.