Introductory Chapter: Noncoding RNAs–A Brief Introduction

1. Introduction

The discovery of ribosomal RNAs (rRNAs) and transfer RNAs (tRNAs) in 1960s led to first steps of noncoding RNA (ncRNA) research [1, 2, 3]. In 1980, 90–220 nucleotides long small nuclear RNAs (snRNAs) were involved in splicing reported by Lerner et al. [4]. When microRNAs (miRNAs) were discovered in the late 1990s, the noncoding RNA research gained a momentum [5, 6]. Furthermore, development of the next-generation sequencing technologies and advanced bioinformatics opens a new era for noncoding RNAs (ncRNAs).

Ubiquitously, ncRNAs are present in all three domains of life and less than 2% of the human genome code for proteins. Generally, ncRNAs do not code for proteins, but there is some exceptions coding for small bioactive peptides [7, 8]. The two major groups of ncRNAs may be separated from each other by having less or more 200 nucleotides (nts): small noncoding RNAs (sncRNAs) are shorter than 200 nts, and long noncoding RNAs (lncRNAs) are longer than 200 nts.

Noncoding RNAs may be grouped into some categories; tRNA (transfer RNA), rRNA (ribosomal RNA), snRNA (small nuclear RNA), snoRNA (small nucleolar RNA), Telomerase RNA, tRF (transfer RNA-derived RNA fragments), and tiRNA (tRNA-derived stress-induced RNAs) are all “housekeeping” RNAs. “Regulatory” RNAs are miRNA (microRNA), siRNA (small interfering RNA), piRNA (P-element-induced wimpy testis (PIWI) interacting RNA), eRNA (enhancer RNA), lncRNA (long noncoding RNA), circRNA (circular RNA), YRNA, crasiRNA (centromere repeat associated short interacting RNA), and TelsRNA (telomere-specific small RNA). Based on structure, LincRNA (long intergenic noncoding RNA), TUCRNA (transcribed ultraconserved RNA), eRNA, and NAT (natural antisense transcript) are “linear” RNAs while ciRNA, ecircRNA (exonic circular RNA), and elciRNA (exon–intron circRNA) are “circular” RNAs. Based on the location, RNAs may be grouped as sense, antisense, intronic, intergenic, and bidirectional RNAs. Some of the ncRNA families are briefly reviewed below. Rfam is a public online database, which provides information for all RNA families, each represented by multiple sequence alignments, consensus secondary structures, and covariance models (https://rfam.xfam.org/) [9].

2. miRNAs (microRNAs)

miRNAs are ~20 nts long molecules that generally regulate gene expression by inducing mRNA degradation or translational repression. miRNAs originated from pri-miRNA and mature miRNAs regulate protein coding genes. Understanding the regulation of gene expression is changed after the discovery of first miRNA called lin-4 on Caenorhabditis elegans in 1993 [5]. Furthermore, miRNAs are potential biomarkers for several human diseases since they are responsible for many biological processes in the cell such as cell differentiation, cell proliferation, cell death, and development by inducing mRNA degradation or translational repression. Especially, oncomirs such as mir-21 are generally upregulated in cancer patients, and miRNAs attract researchers because of their potential as diagnostic and prognostic biomarkers. miRNA gene sequences are publicly deposited on miRBase catalogs (https://www.mirbase.org/) [10].

3. siRNAs (small interfering RNAs)

siRNAs are about 20–22 nts in size and evolved from double-stranded RNAs. They perform silent transcription of genes via inducing mRNA degradation. siRNAs are very attractive for therapeutic applications in cancer and other diseases [11]. Especially, siRNAs target genes within the tumor cells to inhibit expansions of tumors by RNAi (RNA interference) technology [12]. Moreover, RNAi is a powerful tool in agriculture for crop improvement, including development against biotic or abiotic stress, seedless fruit development, improvement of nutritional quality, and induction of male sterility [13]. Furthermore, a database of siRNA sequences called siRNAdb located on http://sirna.cgb.ki.se/ provides information for siRNAs [14].

4. piRNAs (P-element-induced wimpy testis (PIWI) interacting RNAs)

piRNAs are small noncoding RNAs, which originated from long single chain precursor transcripts. These RNAs are about 21–35 nts long and interact with PIWI proteins to form the piRNA silencing complex (piRISC). piRNAs play key roles in transposon repression, DNA methylation, silencing transposable elements, regulating gene expression, and fighting with viral infections. Since their abnormal expression is reported for many cancer types, they have potential to be diagnostic tools, prognostic markers, and therapeutic targets for cancer [15]. There are two important databases for piRNAs on the web, piRNAdb and piRNABank. piRNAdb is a piwi-interacting RNA sequences storage and search system, providing some other relevant information such as alignments, clusters, datasets, and targets of these piRNAs on its URL (https://www.pirnadb.org/index). piRNABank provides comprehensive information on piRNAs in the three widely studied mammals, namely Human, Mouse, Rat and one fruit fly, Drosophila on the http://pirnabank.ibab.ac.in/ web address [16].

5. lncRNAs (long noncoding RNAs)

lncRNAs with longer than 200 nts are not translated into functional proteins and evolved from multiple ways and mainly transcribed by RNA polymerase II (and also by other RNA polymerases). lncRNAs regulate gene expressions in multiple ways including chromatin structure modulation, regulation of function and the transcription of neighboring and distant genes, and alteration of RNA splicing, stability and translation by interacting with DNA, RNA, and proteins. Moreover, lncRNAs can play roles in the formation and regulation of organelles [17]. Furthermore, they take roles in chromatin remodeling, cancer cell invasion and metastasis, and cell differentiation by acting as cis- or trans-regulators in biological processes [18]. lncRNAs are linked to some human diseases including hepatocellular carcinoma, Alzheimer’s disease, and diabetes [19]. Owing to their key roles in diseases, lncRNAs have a potential to be therapeutic targets. Recently, antisense oligonucleotides (ASOs) technology is used to perform therapeutic lncRNA targeting [20, 21]. However, since lncRNAs lack of functional open reading frames, targeting them with CRISPR–Cas system is more difficult compared with targeting protein-coding genes [22]. There are too many lncRNA databases on the internet, but most comprehensive lncRNA database is RNAcentral located at https://rnacentral.org/ on the World Wide Web [23]. RNAcentral offers integrated access to a comprehensive and up-to-date set of ncRNA sequences.

6. Future perspectives

Mounting data, evidence, and recent discoveries of novel short and long regulatory noncoding RNAs have changed the understanding of genome and transcriptome in the cell. Advanced bioinformatics, public databases, and sequencing technologies led to fast understanding of biogenesis and function of ncRNA types and families. ncRNAs are potential biomarkers to perform therapeutic applications for diseases and to improve crops for agriculture. Further illumination of function, biogenesis, and interactions of ncRNAs will empower our understanding of natural dogma with the aid of developing bioinformatics, sequencing, and biochemical techniques.