Epigenetics in Neurodevelopment: Emerging Role of Circular RNA

Abstract

Canonical epigenetic modifications, including DNA methylation, histone modification and chromatin remodeling, play a role in numerous life processes, particularly neurodevelopment. Epigenetics explains the development of cells in an organism with the same DNA sequence into different cell types with various functions. However, previous studies on epigenetics have only focused on the chromatin level. Recently, epigenetic modifications of RNA, which mainly include 6-methyladenosine (m⁶A), pseudouridine, 5-methylcytidine (m⁵C), inosine (I), 2'-O-ribosemethylation, and 1-methyladenosine (m¹A), have gained increasing attention. Circular RNAs (circRNAs), which are a type of non-coding RNA without a 5' cap or 3' poly (A) tail, are abundantly found in the brain and might respond to and regulate synaptic function. Also, circRNAs have various functions, such as microRNA sponge, regulation of gene transcription and interaction with RNA binding protein. In addition, circRNAs are methylated by N ⁶-methyladenosine (m⁶A). In this review, we discuss the crucial roles of epigenetic modifications of circRNAs, such as m⁶A, in the genesis and development of neurons and in synaptic function and plasticity. Thus, this type of changes in circRNAs might be a therapeutic target in central nervous system (CNS) disorders and could aid the diagnosis and treatment of these disorders.

Keywords: circular RNA; epigenomics; m6A; neurodevelopment; non-coding RNA.

FIGURE 1

Canonical epigenetics mechanism. (A) DNA methylation in the CpG and CpH context. (B) Chromatin remodeling is ATP dependent. ATP-dependent remodeling complexes regulate DNA accessibility, and histone chaperones move and transfer histones on and off a locus. An open chromatin structure enables RNA polymerase II to catalyze the transcription when the histone is evicted, while chromatin state change to inactivity to inhibit gene transcription with the histone deposition of chromosome. (C) The acetylation of histone tails by histone acetyltransferases (HATs) establishes a more relaxed state in the chromatin that results in transcriptional activation (activated state). Histone deacetylation by HDACs reverses the activating chromatin state to a “inactive” chromatin state to inhibit gene transcription.

FIGURE 2

N⁶-Methyladenosine modification is always found to occur in the consensus sequence identified as: RRACH (R = G or A; H = A, C or U). M⁶A modification can promote the translation of the circRNAs.

FIGURE 3

Circular RNAs are related to neurodevelopment through different mechanisms. (A) circRNAs regulate the translation of mRNAs by serving as miRNA sponges. (B) Some circRNAs with an IRES sequence can translate proteins, and this translation is driven by IRES. (C) circRNAs may transmit the information to environment by synaptosomes or extracellular vesicle such as exosomes.