The transcriptome of a cell is represented by a myriad of different RNA molecules with and without protein-coding capacities. Before recognition of the versatility of RNA, DNA was considered the sole conveyor of information while RNA was thought to solely function as an intermediate in protein synthesis (mRNA) or as effector molecules (tRNA, rRNA, snRNA). In the past couple of decades, RNA research has shed light on the pliability of RNA and its many regulatory functions in gene expression (Fig. 1). Several classes of noncoding RNAs (ncRNAs) such as microRNAs (miRNAs), piwi-interacting RNAs (piRNAs), and long noncoding RNAs (lncRNAs) have been identified and associated with regulatory functions and diseases.[1] According to current genome annotations, the number of human ncRNAs is much higher than the number of protein-coding genes. The RNA landscape is further enriched by the presence of retrotransposons, a broad class of transposable elements, or “jumping genes,” that duplicate through RNA intermediates that are reverse transcribed and inserted at new genomic locations. Due to their “copy and paste” mechanism, retrotransposons amplify in number quickly, composing 40% of the entire human genome.

Fig1. HIERARCHY OF RNA CLASSES DEFINED BY FUNCTION, BIOGENESIS, AND SIZE. The human genome contains more noncoding RNAs than messenger RNAs. Noncoding RNAs perform multiple functions, essential for both gene expression and its regulation.

LncRNAs are defined by their length, greater than 200 nucleotides (nt). They have gene regulatory roles in the nucleus or function in the cytoplasm via epigenetic, transcriptional, posttranscriptional, translational, and protein location effects. With almost 18,000 genes in the human genome, lncRNAs are apparently the most numerous and functionally diverse class of ncRNAs. Depending on their genomic location, they can be further divided in antisense (asRNAs), overlapping protein coding genes, or intergenic (lincRNAs) (see Fig. 1). Several lncRNAs undergo maturation processes such as capping, splicing, and polyadenylation. Despite their designation as ncRNAs, a considerable number of these transcripts tend to contain short open reading frames (sORFs) and bind with ribosomes, suggesting that the coding potential of lncRNAs has been vastly underestimated. Although the function of most lncRNAs is still unknown, multiple lincRNAs such as MALAT1, NEAT1, or XIST have already been implicated in human diseases such as cancer. An inherited form of α-thalassemia is caused by the translocation of an antisense lncRNA near the α-globin gene, resulting in the epigenetic silencing of the HBA2 gene and causing the disease.

Short ncRNAs, with a length less than 200 nucleotides, account for approximately 8500 genes in the human genome. They include well known RNA classes such as tRNAs and rRNAs, essential for translation and described below in the section Protein Synthesis. snRNAs are associated with specific proteins in snRNPs and part of the spliceosomal complexes described in the section Regulation of RNA Processing: Capping, Splicing and Polyadenylation. Small nucleolar RNAs (snoR NAs) are a class of small RNA molecules that primarily guide chemical modifications of other RNAs, mainly rRNAs, tRNAs, and snRNAs.

More recently discovered classes of short RNAs include miRNAs, siRNAs, and piRNAs. The role of miRNAs and siRNAs are described in detail later (section RNA Interference). piRNAs are approximately 26- to 31-nt-long transcripts and function in suppression of transposable elements and maintenance of germline integrity.

Among emerging classes of RNAs, circular RNAs (circRNAs) are primarily produced via backsplicing of the 3′ end to the 5′ end of exons within the same transcript of a coding gene, giving these RNAs the circular shape. Compared with linear RNA, circRNAs form a covalently closed circular continuous loop and are highly conserved, stable, and tissue specific. CircRNAs can result in alternative protein isoforms and function as decoys for miRNAs and RNA-binding proteins, thereby regulating RNA stability and translation.

Enhancer RNAs (eRNAs) are generally relatively short ncRNAs transcribed from the genomic DNA at enhancer regions and rep resent a diverse class of molecules. They were originally described as nonpolyadenylated, bidirectionally transcribed RNA transcripts (4000 nt), polyadenylated, and unidirectionally transcribed from higher-activity enhancers. eRNAs can regulate transcription in cis and in trans. Studies to identify their specific functions and mechanisms of action are ongoing.

ncRNAs, that once were mostly considered “junk” because they were diverging from the “central dogma,” are proving to be an increasingly important part of our genome, an intricate layer of signals that control gene expression in physiology and disease.

References

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[1] Hombach S, Kretz M. Non-coding RNAs: classification, biology and functioning. Adv Exp Med Biol. 2016;937:3–17.

مواضيع ذات صلة

Nuclear Export of RNA

Regulation of RNA Processing: Capping, Splicing, and Polyadenylation

The Alpha Helix, Beta Sheet, and Beta Turn

Structures within Proteins

تصميم البوادئ primer design

كيف نعرف تسلسل الجين

Control of Gene Function and Biochemical Activity in Cells

آليات إصلاح الحمض النووي المتضرر DNA repair mechanisms

Hydrophobic Forces

Hydrogen Bonds and the Chelate Effect

Genes in the Cell Nucleus Control Protein Synthesis

RNA Proofreading