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Review
. 2024 Jul 19;35(3):102281.
doi: 10.1016/j.omtn.2024.102281. eCollection 2024 Sep 10.

Insights into the regulatory role of epigenetics in moyamoya disease: Current advances and future prospectives

Shuangxiang Xu  1   2 , Tongyu Chen  1   2 , Jin Yu  2 , Lei Wan  2 , Jianjian Zhang  2 , Jincao Chen  1   2 , Wei Wei  1   2 , Xiang Li  1   2   3   4   5
Affiliations
Review

Insights into the regulatory role of epigenetics in moyamoya disease: Current advances and future prospectives

Shuangxiang Xu et al. Mol Ther Nucleic Acids. .

Abstract

Moyamoya disease (MMD) is a progressive steno-occlusive cerebrovascular disorder that predominantly affecting East Asian populations. The intricate interplay of distinct and overlapping mechanisms, including genetic associations such as the RNF213-p.R4810K variant, contributes to the steno-occlusive lesions and moyamoya vessels. However, genetic mutations alone do not fully elucidate the occurrence of MMD, suggesting a potential role for epigenetic factors. Accruing evidence has unveiled the regulatory role of epigenetic markers, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs), in regulating pivotal cellular and molecular processes implicated in the pathogenesis of MMD by modulating endothelial cells and smooth muscle cells. The profile of these epigenetic markers in cerebral vasculatures and circulation has been determined to identify potential diagnostic biomarkers and therapeutic targets. Furthermore, in vitro studies have demonstrated the multifaceted effects of modulating specific epigenetic markers on MMD pathogenesis. These findings hold great potential for the discovery of novel therapeutic targets, translational studies, and clinical applications. In this review, we comprehensively summarize the current understanding of epigenetic mechanisms, including DNA methylation, histone modifications, and ncRNAs, in the context of MMD. Furthermore, we discuss the potential challenges and opportunities that lie ahead in this rapidly evolving field.

Keywords: DNA methylation; MT: Novel therapeutic targets and biomarker development Special Issue; epigenetics; histone modification; moyamoya disease; non-coding RNA.

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Conflict of interest statement

The authors declare no conflict of interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
The biogenesis and functions of miRNAs Canonically, miRNA genes are first transcribed by RNA polymerase II (Pol II) in the nucleus, resulting in primary miRNA (pri-miRNAs) transcripts that contain stem-loop structures. Next, the nuclear microprocessor, consisting of RNase III enzyme Drosha and its cofactor DGCR8, identifies and cleaves these stem-loop structures to release a precursor miRNA (pre-miRNA). The pre-miRNA is then transported into the cytoplasm by Exportin-5 and cleaved near the terminal loop by the RNase III enzyme Dicer, leaving an miRNA duplex. The guide strand is loaded into an Argonaute (Ago) protein to form the core of the silencing complex, while the complementary strand is discarded and degraded. Noncanonical processing pathways of miRNA biogenesis involve the generation of pre-miRNA hairpins independent of Drosha through the processing of mirtrons, which are pre-miRNA mimics generated by the spliceosome and intron-debranching enzymes. (A) The canonical function of miRNAs is to target the 3′ untranslated region (UTR) of target mRNAs, causing mRNA degradation or translational repression. (B) Noncanonically, certain miRNAs can target the coding sequence (CDS) of their target mRNA, resulting in mRNA degradation or translational repression, as illustrated for miR-20a binding to the CDS of DAPK3 mRNA causing its translational repression by inducing transient ribosome stalling. (C) A class of miRNAs can also target the 5′ UTR of their target mRNA, resulting in translational activation. For example, miR-10a can interact with the 5′ UTR of mRNAs encoding ribosomal proteins to enhance their translation. (D) Some miRNAs can be secreted into extracellular vesicles and directly target Toll-like receptors (TLRs) by acting as their ligands, in turn activating TLR signaling pathways and inducing an immune response.
Figure 2
Figure 2
The biogenesis and functions of lcnRNAs Similar to mRNAs, most lncRNAs are transcribed by RNA Pol II from various genomic loci with similar chromatin states to mRNA. In general, lncRNAs can be transcribed in sense or antisense directions from introns or exons of overlapping protein-coding genes. It is worthwhile noting that different DNA elements, such as intergenic regions, promoters, and enhancers, are also transcribed into several distinct classes of lncRNAs in eukaryotic genomes. (A) lncRNAs can modulate chromatin structure and function by interacting with targeted DNA regions. For example, the lncRNA HOTTIP interacts with WD repeat-containing protein 5 (WDR5), thereby guiding the histone methyltransferase complex WDR5--MLL (myeloid/lymphoid leukemia) to the promoters of HOXA genes to promote its transcription. (B) A certain class of lncRNAs play its regulatory activity through the formation of RNA-DNA triplexes. For instance, lncRNA MEG3 possessed GA-rich sequences in binding sites, which guide MEG3 to the chromatin through RNA-DNA triplex formation, and recruit PRC2 to distal regulatory elements, thereby establishing H3K27me3 marks to modulate the activity of TGF-β genes. (C) Some lncRNAs can directly combine other RNAs by base pairing and affect RNA stability. For example, lncRNA TINCR contains several 25-nucleotide motifs that base pair with complementary sequences in differentiation mRNAs and then recruit STAU1 (Staufen homolog 1) to group TINCR-STAU1 complex to stabilize the differentiation mRNAs. (D) Acting as a miRNA sponge, as illustrated for lncRNA H19 competitively sponging miR-106a-5p to activate Runx2 (runt-related transcription factor-2)-dependent VSMC osteogenic differentiation and vascular calcification. (E) Certain lncRNAs can serve as molecular scaffolds to provide a platform for protein interactions. For example, lncRNA JPX acts as a molecular scaffold for the local recruitment of the chromatin remodeling complex comprising phosphorylated p65 and BRD4 (bromodomain-containing protein 4) to the enhancers of the senescence-associated secretory phenotype (SASP) gene, activating the transcription of SASP and promoting cellular senescence in VSMCs. (F) Some lncRNAs have small open reading frames that can be translated by ribosomes to encode peptides. For example, lncPSR encoded a peptide named Arteridin, which could regulate downstream genes (such as ACTA2, KLF5) by directly interacting with a transcription factor YBX1 (Y-box binding protein 1) and modulating its nuclear translocation and chromatin targeting, thus inducing VSMC phenotype switching and vascular remodeling. (G) In the cytoplasm, lncRNAs can undergo specific sorting processes that assign different lncRNAs to specific organelles (e.g., mitochondria, exosomes).
Figure 3
Figure 3
The biogenesis and functions of circRNAs circRNAs are produced by precursor mRNA (pre-mRNA) through a “back-splicing” process, where the downstream 5′ splicing donor is connected to the upstream 3′ splicing acceptor via a 3' → 5′ phosphodiester bond at the back-splicing junction site. The circularization of the exons to form an exonic circRNAs (ecircRNAs) is mediated by the flanking inverted complementary repeats sequence (such as Alu elements) and RNA binding proteins (RBPs). Another formation of circRNAs is associated with exon skipping, in which a lariat precursor containing one or more skipped exons is first generated. Then the lariat removes its internal intron sequences, generating a mature circRNA and a double lariat. In some cases, the intervening introns in the encircled exons are not removed, which produces so-called EIciRNAs. (A) Classically, circRNAs can serve as sponges for miRNAs, as demonstrated by ciRS-7, which harbors target sites for miR-7. (B) A class of nuclear-localized EIciRNAs could regulate the transcription of their parental genes via specific RNA-RNA interaction. For example, EIciEIF3J can control the transcription level of its parent gene EIF3J by interacting with the Pol II and U1 small ribonucleoprotein particle (U1snRNP). (C) Certain circRNAs are also able to act as protein sponges. For example, circCDYL was almost completely covered with binding sites of a multifunctional RBP GRWD1. The interaction between circCDYL and GRWD1 could negatively regulate the key cancer gene TP53 and promote tumorigenesis. (D) circRNAs can undergo translation and produce small peptides, as demonstrated by circE-Cad encoding a specific secretory E-cadherin protein variant, which contains a unique 14-amino-acid C terminus. (E) Some circRNAs can be secreted in various physiological fluids (including blood, plasma, CSF, and urine samples) and may serve as novel diagnostic and prognostic biomarkers.
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