Long Non-Coding RNA Epigenetics

Abstract

Long noncoding RNAs exceeding a length of 200 nucleotides play an important role in ensuring cell functions and proper organism development by interacting with cellular compounds such as miRNA, mRNA, DNA and proteins. However, there is an additional level of lncRNA regulation, called lncRNA epigenetics, in gene expression control. In this review, we describe the most common modified nucleosides found in lncRNA, 6-methyladenosine, 5-methylcytidine, pseudouridine and inosine. The biosynthetic pathways of these nucleosides modified by the writer, eraser and reader enzymes are important to understanding these processes. The characteristics of the individual methylases, pseudouridine synthases and adenine-inosine editing enzymes and the methods of lncRNA epigenetics for the detection of modified nucleosides, as well as the advantages and disadvantages of these methods, are discussed in detail. The final sections are devoted to the role of modifications in the most abundant lncRNAs and their functions in pathogenic processes.

Keywords: RNA modyfiing enzymes; detection modified nucleotides; lncRNA epigenetics.

Figure 1

The structure of modified nucleotides found in eukaryotic lncRNA molecules [26,27,28,29].

Figure 2

The crystal structure of “writer” enzymes, forming the following lncRNA modifications: (A)—METTL3/METTL14 m⁶A methyltransferase [41]; (B)—PSU1 pseudouridine synthase [42]; and (C)—ADAR1 A-I editing adenosine deaminase [43].

Figure 3

Schematic of lncRNA modification pathways. Writer, reader and eraser proteins are shown. Nucleotides: A—adenosine; C—cytidine; U—uridine. Modifications: m⁶A—6-methyladenosine; m⁵C—5-methylcytosine; Ψ—pseudouridine; I—inosine; hm⁵C—5-hydroxymethylcytidine. Writer proteins: METTL3, 14, 16 methyltransferase-like; WTAP—Wilms’ tumor 1 associating protein; KIAA1429—methyltransferase; RBM 15—RNA-binding motif protein 15 and its paralog RBM15B; NSUN—NOL1/NOP2/SUN domain family member; PUS—pseudouridine synthase; ADAR1, ADAR2—adenosine deaminase acting on RNA. Reader proteins: YTHDC, YTHDF—subgroups of YTH domain containing proteins; ZCCHC4—zinc-finger CCHC domain-containing protein 4; eIF3—eukaryotic initiation factor 3; hnRNPA2B1 and hnRNPC—heterogeneous nuclear ribonucleoproteins; ALYREF—ALY/REF export factor. Eraser proteins: FTO—fat mass and obesity-associated protein; ALKBH5—alpha-ketoglutarate-dependent dioxygenase AlkB homolog 5; TET—ten–eleven translocation protein.