Small RNA

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Small RNA (sRNA) are polymeric RNA molecules that are less than 200 nucleotides in length, and are usually non-coding. [1] RNA silencing is often a function of these molecules, with the most common and well-studied example being RNA interference (RNAi), in which endogenously expressed microRNA (miRNA) or exogenously derived small interfering RNA (siRNA) induces the degradation of complementary messenger RNA. Other classes of small RNA have been identified, including piwi-interacting RNA (piRNA) and its subspecies repeat associated small interfering RNA (rasiRNA). [2] Small RNA "is unable to induce RNAi alone, and to accomplish the task it must form the core of the RNA–protein complex termed the RNA-induced silencing complex (RISC), specifically with Argonaute protein". [3] : 366 

Small RNA have been detected or sequenced using a range of techniques, including directly by MicroRNA sequencing on several sequencing platforms, [4] [5] [6] or indirectly through genome sequencing and analysis. [7] Identification of miRNAs has been evaluated in detecting human disease, such as breast cancer. [5] Peripheral blood mononuclear cell (PBMC) miRNA expression has been studied as potential biomarker for different neurological disorders such as Parkinson's disease, [8] Multiple sclerosis. [9] Evaluating small RNA is useful for certain kinds of study because its molecules "do not need to be fragmented prior to library preparation". [3] : 162 

Types of small RNA include:

In plants

The first known function in plants was discovered in mutants of Arabidopsis . Specifically with decline in function mutations for RNA-dependent RNA polymerase and DICER-like production. This impairment actually enhanced Arabidopsis resistance against Heterodera schachtii and Meloidogyne javanica . Similarly, mutants with reduced Argonaute function - ago1-25 , ago1-27 , ago2-1 , and combined mutants with ago1-27 and ago2-1 - had greater resistance to Meloidogyne incognita . Altogether this demonstrates great dependence of nematode parasitism on plants' own small RNAs. [14]

Related Research Articles

microRNA Small non-coding ribonucleic acid molecule

MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRNAs base-pair to complementary sequences in mRNA molecules, then gene silence said mRNA molecules by one or more of the following processes:

  1. Cleavage of mRNA strand into two pieces,
  2. Destabilization of mRNA by shortening its poly(A) tail, or
  3. Translation of mRNA into proteins.

Gene silencing is the regulation of gene expression in a cell to prevent the expression of a certain gene. Gene silencing can occur during either transcription or translation and is often used in research. In particular, methods used to silence genes are being increasingly used to produce therapeutics to combat cancer and other diseases, such as infectious diseases and neurodegenerative disorders.

<span class="mw-page-title-main">Small interfering RNA</span> Biomolecule

Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20-24 base pairs in length, similar to miRNA, and operating within the RNA interference (RNAi) pathway. It interferes with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, preventing translation.

<span class="mw-page-title-main">Dicer</span> Enzyme that cleaves double-stranded RNA (dsRNA) into short dsRNA fragments

Dicer, also known as endoribonuclease Dicer or helicase with RNase motif, is an enzyme that in humans is encoded by the DICER1 gene. Being part of the RNase III family, Dicer cleaves double-stranded RNA (dsRNA) and pre-microRNA (pre-miRNA) into short double-stranded RNA fragments called small interfering RNA and microRNA, respectively. These fragments are approximately 20–25 base pairs long with a two-base overhang on the 3′-end. Dicer facilitates the activation of the RNA-induced silencing complex (RISC), which is essential for RNA interference. RISC has a catalytic component Argonaute, which is an endonuclease capable of degrading messenger RNA (mRNA).

The RNA-induced silencing complex, or RISC, is a multiprotein complex, specifically a ribonucleoprotein, which functions in gene silencing via a variety of pathways at the transcriptional and translational levels. Using single-stranded RNA (ssRNA) fragments, such as microRNA (miRNA), or double-stranded small interfering RNA (siRNA), the complex functions as a key tool in gene regulation. The single strand of RNA acts as a template for RISC to recognize complementary messenger RNA (mRNA) transcript. Once found, one of the proteins in RISC, Argonaute, activates and cleaves the mRNA. This process is called RNA interference (RNAi) and it is found in many eukaryotes; it is a key process in defense against viral infections, as it is triggered by the presence of double-stranded RNA (dsRNA).

<span class="mw-page-title-main">Argonaute</span> Protein that plays a role in RNA silencing process

The Argonaute protein family, first discovered for its evolutionarily conserved stem cell function, plays a central role in RNA silencing processes as essential components of the RNA-induced silencing complex (RISC). RISC is responsible for the gene silencing phenomenon known as RNA interference (RNAi). Argonaute proteins bind different classes of small non-coding RNAs, including microRNAs (miRNAs), small interfering RNAs (siRNAs) and Piwi-interacting RNAs (piRNAs). Small RNAs guide Argonaute proteins to their specific targets through sequence complementarity, which then leads to mRNA cleavage, translation inhibition, and/or the initiation of mRNA decay.

Piwi-interacting RNA (piRNA) is the largest class of small non-coding RNA molecules expressed in animal cells. piRNAs form RNA-protein complexes through interactions with piwi-subfamily Argonaute proteins. These piRNA complexes are mostly involved in the epigenetic and post-transcriptional silencing of transposable elements and other spurious or repeat-derived transcripts, but can also be involved in the regulation of other genetic elements in germ line cells.

<span class="mw-page-title-main">Piwi</span>

Piwi genes were identified as regulatory proteins responsible for stem cell and germ cell differentiation. Piwi is an abbreviation of P-elementInduced WImpy testis in Drosophila. Piwi proteins are highly conserved RNA-binding proteins and are present in both plants and animals. Piwi proteins belong to the Argonaute/Piwi family and have been classified as nuclear proteins. Studies on Drosophila have also indicated that Piwi proteins have no slicer activity conferred by the presence of the Piwi domain. In addition, Piwi associates with heterochromatin protein 1, an epigenetic modifier, and piRNA-complementary sequences. These are indications of the role Piwi plays in epigenetic regulation. Piwi proteins are also thought to control the biogenesis of piRNA as many Piwi-like proteins contain slicer activity which would allow Piwi proteins to process precursor piRNA into mature piRNA.

RNA-induced transcriptional silencing (RITS) is a form of RNA interference by which short RNA molecules – such as small interfering RNA (siRNA) – trigger the downregulation of transcription of a particular gene or genomic region. This is usually accomplished by posttranslational modification of histone tails which target the genomic region for heterochromatin formation. The protein complex that binds to siRNAs and interacts with the methylated lysine 9 residue of histones H3 (H3K9me2) is the RITS complex.

RNA silencing or RNA interference refers to a family of gene silencing effects by which gene expression is negatively regulated by non-coding RNAs such as microRNAs. RNA silencing may also be defined as sequence-specific regulation of gene expression triggered by double-stranded RNA (dsRNA). RNA silencing mechanisms are conserved among most eukaryotes. The most common and well-studied example is RNA interference (RNAi), in which endogenously expressed microRNA (miRNA) or exogenously derived small interfering RNA (siRNA) induces the degradation of complementary messenger RNA. Other classes of small RNA have been identified, including piwi-interacting RNA (piRNA) and its subspecies repeat associated small interfering RNA (rasiRNA).

RNA activation (RNAa) is a small RNA-guided and Argonaute (Ago)-dependent gene regulation phenomenon in which promoter-targeted short double-stranded RNAs (dsRNAs) induce target gene expression at the transcriptional/epigenetic level. RNAa was first reported in a 2006 PNAS paper by Li et al. who also coined the term "RNAa" as a contrast to RNA interference (RNAi) to describe such gene activation phenomenon. dsRNAs that trigger RNAa have been termed small activating RNA (saRNA). Since the initial discovery of RNAa in human cells, many other groups have made similar observations in different mammalian species including human, non-human primates, rat and mice, plant and C. elegans, suggesting that RNAa is an evolutionarily conserved mechanism of gene regulation.

<span class="mw-page-title-main">Y RNA</span>

Y RNAs are small non-coding RNAs. They are components of the Ro60 ribonucleoprotein particle which is a target of autoimmune antibodies in patients with systemic lupus erythematosus. They are also reported to be necessary for DNA replication through interactions with chromatin and initiation proteins. However, mouse embryonic stem cells lacking Y RNAs are viable and have normal cell cycles.

<span class="mw-page-title-main">EIF2C2</span> Protein-coding gene in the species Homo sapiens

Protein argonaute-2 is a protein that in humans is encoded by the EIF2C2 gene.

<span class="mw-page-title-main">EIF2C1</span> Protein-coding gene in the species Homo sapiens

Protein argonaute-1 is a protein that in humans is encoded by the EIF2C1 gene.

<span class="mw-page-title-main">RNA interference</span> Biological process of gene regulation

RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by other names, including co-suppression, post-transcriptional gene silencing (PTGS), and quelling. The detailed study of each of these seemingly different processes elucidated that the identity of these phenomena were all actually RNAi. Andrew Fire and Craig C. Mello shared the 2006 Nobel Prize in Physiology or Medicine for their work on RNAi in the nematode worm Caenorhabditis elegans, which they published in 1998. Since the discovery of RNAi and its regulatory potentials, it has become evident that RNAi has immense potential in suppression of desired genes. RNAi is now known as precise, efficient, stable and better than antisense therapy for gene suppression. Antisense RNA produced intracellularly by an expression vector may be developed and find utility as novel therapeutic agents.

In molecular biology mir-390 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

Transposon silencing is a form of transcriptional gene silencing targeting transposons. Transcriptional gene silencing is a product of histone modifications that prevent the transcription of a particular area of DNA. Transcriptional silencing of transposons is crucial to the maintenance of a genome. The “jumping” of transposons generates genomic instability and can cause extremely deleterious mutations. Transposable element insertions have been linked to many diseases including hemophilia, severe combined immunodeficiency, and predisposition to cancer. The silencing of transposons is therefore extremely critical in the germline in order to stop transposon mutations from developing and being passed on to the next generation. Additionally, these epigenetic defenses against transposons can be heritable. Studies in Drosophila, Arabidopsis thaliana, and mice all indicate that small interfering RNAs are responsible for transposon silencing. In animals, these siRNAS and piRNAs are most active in the gonads.

RDE-1 (RNAi-DEfective 1) is a primary Argonaute protein required for RNA-mediated interference (RNAi) in Caenorhabditis elegans. The rde-1 gene locus was first characterized in C. elegans mutants resistant to RNAi, and is a member of a highly conserved Piwi gene family that includes plant, Drosophila, and vertebrate homologs.

piwi-interacting RNA (piRNA) belongs to the small RNA class found in eukaryotic organisms, their major role is to regulate the expression of genes by the mRNA degradation or silencing. After the association with argonaute protein family, these short RNA guide the RNA-induced silencing complex (RISC) to their target by sequence complementarity. piRNAs have approximately from 26 to 31 nucleotides and are found in almost all metazoans.

<span class="mw-page-title-main">RNA-directed DNA methylation</span> RNA-based gene silencing process

RNA-directed DNA methylation (RdDM) is a biological process in which non-coding RNA molecules direct the addition of DNA methylation to specific DNA sequences. The RdDM pathway is unique to plants, although other mechanisms of RNA-directed chromatin modification have also been described in fungi and animals. To date, the RdDM pathway is best characterized within angiosperms, and particularly within the model plant Arabidopsis thaliana. However, conserved RdDM pathway components and associated small RNAs (sRNAs) have also been found in other groups of plants, such as gymnosperms and ferns. The RdDM pathway closely resembles other sRNA pathways, particularly the highly conserved RNAi pathway found in fungi, plants, and animals. Both the RdDM and RNAi pathways produce sRNAs and involve conserved Argonaute, Dicer and RNA-dependent RNA polymerase proteins.

References

  1. ↑ Storz G (May 2002). "An expanding universe of noncoding RNAs". Science. 296 (5571): 1260–3. Bibcode:2002Sci...296.1260S. doi:10.1126/science.1072249. PMID   12016301. S2CID   35295924.
  2. ↑ Gunawardane LS, Saito K, Nishida KM, Miyoshi K, Kawamura Y, Nagami T, et al. (March 2007). "A slicer-mediated mechanism for repeat-associated siRNA 5' end formation in Drosophila". Science. 315 (5818): 1587–90. doi: 10.1126/science.1140494 . PMID   17322028. S2CID   11513777.
  3. 1 2 Meyers RA (2012). Epigenetic Regulation and Epigenomics. Wiley-Blackwell. ISBN   978-3-527-66861-8.
  4. ↑ Lu C, Tej SS, Luo S, Haudenschild CD, Meyers BC, Green PJ (September 2005). "Elucidation of the small RNA component of the transcriptome". Science. 309 (5740): 1567–9. Bibcode:2005Sci...309.1567L. doi:10.1126/science.1114112. PMID   16141074. S2CID   1651848.
  5. 1 2 Wu Q, Lu Z, Li H, Lu J, Guo L, Ge Q (2011). "Next-generation sequencing of microRNAs for breast cancer detection". Journal of Biomedicine & Biotechnology. 2011: 597145. doi: 10.1155/2011/597145 . PMC   3118289 . PMID   21716661.
  6. ↑ Ruby JG, Jan C, Player C, Axtell MJ, Lee W, Nusbaum C, et al. (December 2006). "Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C. elegans". Cell. 127 (6): 1193–207. doi: 10.1016/j.cell.2006.10.040 . PMID   17174894. S2CID   16838469.
  7. ↑ Witten D, Tibshirani R, Gu SG, Fire A, Lui WO (May 2010). "Ultra-high throughput sequencing-based small RNA discovery and discrete statistical biomarker analysis in a collection of cervical tumours and matched controls". BMC Biology. 8 (1): 58. doi:10.1186/1741-7007-8-58. PMC   2880020 . PMID   20459774.
  8. ↑ Gui Y, Liu H, Zhang L, Lv W, Hu X (November 2015). "Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease". Oncotarget. 6 (35): 37043–53. doi:10.18632/oncotarget.6158. PMC   4741914 . PMID   26497684.
  9. ↑ Keller A, Leidinger P, Lange J, Borries A, Schroers H, Scheffler M, et al. (October 2009). "Multiple sclerosis: microRNA expression profiles accurately differentiate patients with relapsing-remitting disease from healthy controls". PLOS ONE. 4 (10): e7440. Bibcode:2009PLoSO...4.7440K. doi: 10.1371/journal.pone.0007440 . PMC   2757919 . PMID   19823682.
  10. ↑ Green, D; Dalmay, T; Chapman, T (February 2016). "Microguards and micromessengers of the genome". Heredity. 116 (2): 125–134. doi: 10.1038/hdy.2015.84 .
  11. ↑ Wei H, Zhou B, Zhang F, Tu Y, Hu Y, Zhang B, Zhai Q (2013). "Profiling and identification of small rDNA-derived RNAs and their potential biological functions". PLOS ONE. 8 (2): e56842. Bibcode:2013PLoSO...856842W. doi: 10.1371/journal.pone.0056842 . PMC   3572043 . PMID   23418607.
  12. ↑ Green, Darrell; Fraser, William D.; Dalmay, Tamas (June 2016). "Transfer RNA-derived small RNAs in the cancer transcriptome". Pflügers Archiv: European Journal of Physiology. 468 (6): 1041–1047. doi: 10.1007/s00424-016-1822-9 .
  13. ↑ Billmeier, Martina; Green, Darrell; Hall, Adam E.; Turnbull, Carly; Singh, Archana; Xu, Ping; Moxon, Simon; Dalmay, Tamas (31 December 2022). "Mechanistic insights into non-coding Y RNA processing". RNA Biology. 19 (1): 468–480. doi: 10.1080/15476286.2022.2057725 . PMID   35354369.
  14. ↑ Hewezi T (2020-08-25). "Epigenetic Mechanisms in Nematode–Plant Interactions". Annual Review of Phytopathology . Annual Reviews. 58 (1): 119–138. doi:10.1146/annurev-phyto-010820-012805. ISSN   0066-4286. PMID   32413274. S2CID   218658491.


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