FTO, RNA epigenetics and epilepsy

Abstract

Several recent landmark papers describing N6-methyladenosine (m6A) RNA modifications have provided valuable new insights as to the importance of m6A in the RNA transcriptome and in furthering the understanding of RNA epigenetics. One endogenous enzyme responsible for demethylating RNA m6A, FTO, is highly expressed in the CNS and is likely involved in mRNA metabolism, splicing or other nuclear RNA processing events. microRNAs (miRNAs), a family of small, non-coding transcripts that bind to target mRNAs and inhibit subsequent translation, are highly expressed in the CNS and are associated with several neurological disorders, including epilepsy. miRNAs frequently bind to recognition sequences in the 3′UTR, a region that is also enriched for m6A. Certain specific miRNAs are upregulated by neuronal activity and are coupled to epileptogenesis; these miRNAs contain a consensus m6A site that if methylated could possibly regulate miRNA processing or function. This commentary highlights aspects from recent papers to propose a functional association between FTO, RNA epigenetics and epilepsy.

Epigenetic Downregulation of Scn3a Expression by Valproate: a Possible Role in Its Anticonvulsant Activity

“…In view of the fact that fat mass and obesity-associated (FTO) protein is strongly associated with body weight mass [32][33][34][35][36], and FTO has been shown to catalyze m 6 A demethylation on RNAs [37,38]; thus, it is possible that VPA could posttranscriptionally regulate gene expression through a FTO-mediated epigenetic pathway, since a link between FTO, RNA epigenetics, and epilepsy has been previously put forward [39].…”

Epitranscriptome and FMRP Regulated mRNA Translation

“…Although there is no direct evidence of m 6 A methylation affecting TDP-43/FMRP-regulated neuronal translation or neurological disorders, it should be noted that in human cells more than 12,000 m 6 A sites in about 7000 mRNAs have been identified [119] and the most of m 6 A RNA methylation found in the last exons. This might influence 3 -UTR-mediated translational regulation of mRNAs [120,121]. Therefore, m 6 A methylation potentially exerts fine-tuning on the dendritic translation mechanisms by inhibiting mRNA binding of TDP-43 at the 3 UTR region.…”

m6a RNA Methylation: The Implications for Health and Disease

“…Although FTO is one of the major players in the regulation of m 6 A modification of RNA, it would appear that a secondary signal is required to regulate its activity possibly in response to nutritional stress. With regard to FTO activity in the brain it has recently been linked, along with the m 6 A modification of RNA, to epilepsy [4]. A modification on the DA signalling system gives it a broad reach, not least in the function and activity of the immune system.…”

“…Without further information this proximity may well be circumstantial and irrelevant, however the occurrence of both together is higher than would be expected by chance alone. Even more intriguingly, some miRNAs themselves contain a m 6 A recognition site which may represent a mechanism for their regulation [4]. The m 6 A modification has been demonstrated in a broad range of species including humans [5], mice [5], virii [6,7], yeast [8][9][10], bacteria [11] and plants [12].…”