Small RNA

For the RNA formerly known as sRNA, see soluble RNA.

See also: Bacterial small RNA

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 (from within the organism) expressed microRNA (miRNA) or endogenously/exogenously (from outside the organism) derived small interfering RNA (siRNA) induces the degradation of complementary messenger RNA. ^[2] Other classes of small RNA have been identified, including piwi-interacting RNA (piRNA) and its subspecies repeat associated small interfering RNA (rasiRNA). ^[3] 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". ^{[4] : 366}

A simplified overview of RNAi.

Small RNA have been detected or sequenced using a range of techniques, including directly by MicroRNA sequencing on several sequencing platforms, ^{[5] [6] [7]} or indirectly through genome sequencing and analysis. ^[8] Identification of miRNAs has been evaluated in detecting human disease, such as breast cancer. ^[6] Peripheral blood mononuclear cell (PBMC) miRNA expression has been studied as potential biomarker for different neurological disorders such as Parkinson's disease, ^[9] Multiple sclerosis. ^[10] Evaluating small RNA is useful for certain kinds of study because its molecules "do not need to be fragmented prior to library preparation". ^{[4] : 162}

Discovery

The first sRNA discovered was in 1984 where MicF was found to regulate the outer cell membrane in E. Coli by inhibiting the production of the protein ompF and ompC. ^[11] The use of sRNA in regulation of gene expression was found alongside its discovery. It was later discovered to be present across all eukaryotic organisms. In 1998 it was discovered that the sRNA can be transferred between organisms. It was later discovered in 2011 that sRNA are transferred from cell to cell inside an organism as well. ^[12]

Types of small RNA

• miRNA: microRNA - an RNA involved in RNAi through gene regulation as well as mRNA degradation ^{[13] [14] [15]}
• piRNA: Piwi-interacting RNA - an RNA that regulates the germ line, transposons, as well as histones. It also participates in the argonaute complex. ^[16]
• rasiRNA: repeat-associated siRNAs (a synonym of piRNA)
• qiRNA: QDE-2 interfering RNA - an RNA that regulates gene expression after DNA damage ^[17]
• scRNA: small-scan RNA - ~28-nt RNAs that have been found in Tetrahymena thermophila and that might be involved in scanning DNA sequences in order to induce genome rearrangement. ^[18]
• shRNA: Short hairpin RNA - an RNA that acts similarly to miRNA, regulating gene expression via RISC ^[19]
• siRNA: small interfering RNA - an RNA that regulates both gene expression with RISC ^[20] and by histone modifications. ^[21]
• snRNA: small nuclear RNA, also commonly referred to as U-RNA - an RNA integral to the splicosome, that also stabilizes mRNA ^[22]
• snoRNA: small nucleolar RNA - an RNA regulates the rRNA as well as aiding alternative splicing. It also aids in mRNA degradation. ^[23]
• srRNA: small rDNA-derived RNA - an RNA involved in multiple signaling pathways as well as the formation of Argonaute protein complexes. ^[24]
• tasiRNA: trans-acting siRNAs, a somewhat unspecific terms as many small RNAs are trans-acting. ^[25]
• tiRNA: tRNA-derived stress induced RNA - an RNA that regulates translation by binding to ribosomes. ^[26]
• tRF: tRNA fragment - an RNA fragment that regulates translation by binding to ribosomes and altering mRNA's caps. It can also combine with Argonaute protein complexes to degrade mRNA. ^{[26] [27]}
• ysRNA: Y RNA-derived small RNA - an RNA that aids in initiaion of DNA replication as well as preventing mRNA from degrading. ^{[28] [29]}

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. ^[30]

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. Billi, Allison C.; Fischer, Sylvia E. J.; Kim, John K. (2018), "Endogenous RNAi pathways in C. elegans", WormBook: The Online Review of C. elegans Biology [Internet], WormBook, pp. 1–49, doi:10.1895/wormbook.1.170.1, PMC   4781133 , PMID   24816713 , retrieved 2025-05-05
3. 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.
4. Meyers RA (2012). Epigenetic Regulation and Epigenomics. Wiley-Blackwell. ISBN   978-3-527-66861-8.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. Mizuno, T; Chou, M Y; Inouye, M (April 1984). "A unique mechanism regulating gene expression: translational inhibition by a complementary RNA transcript (micRNA)". Proceedings of the National Academy of Sciences. 81 (7): 1966–1970. Bibcode:1984PNAS...81.1966M. doi: 10.1073/pnas.81.7.1966 . PMC   345417 . PMID   6201848.
12. Zeng, Jun; Gupta, Vijai Kumar; Jiang, Yueming; Yang, Bao; Gong, Liang; Zhu, Hong (2019-04-23). "Cross-Kingdom Small RNAs Among Animals, Plants and Microbes". Cells. 8 (4): 371. doi: 10.3390/cells8040371 . ISSN   2073-4409. PMC   6523504 . PMID   31018602.
13. Lim, Lee P.; Lau, Nelson C.; Garrett-Engele, Philip; Grimson, Andrew; Schelter, Janell M.; Castle, John; Bartel, David P.; Linsley, Peter S.; Johnson, Jason M. (2005-02-17). "Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs". Nature. 433 (7027): 769–773. Bibcode:2005Natur.433..769L. doi:10.1038/nature03315. ISSN   1476-4687. PMID   15685193.
14. Green, D; Dalmay, T; Chapman, T (February 2016). "Microguards and micromessengers of the genome". Heredity. 116 (2): 125–134. Bibcode:2016Hered.116..125G. doi: 10.1038/hdy.2015.84 . PMC   4806885 . PMID   26419338.
15. Iwakawa, Hiro-oki; Tomari, Yukihide (2022-01-06). "Life of RISC: Formation, action, and degradation of RNA-induced silencing complex". Molecular Cell. 82 (1): 30–43. doi: 10.1016/j.molcel.2021.11.026 . ISSN   1097-2765. PMID   34942118.
16. Wu, Xi; Pan, Yutian; Fang, Yuan; Zhang, Jingxin; Xie, Mengyan; Yang, Fengming; Yu, Tao; Ma, Pei; Li, Wei; Shu, Yongqian (2020-09-04). "The Biogenesis and Functions of piRNAs in Human Diseases". Molecular Therapy - Nucleic Acids. 21: 108–120. doi:10.1016/j.omtn.2020.05.023. ISSN   2162-2531. PMC   7283962 . PMID   32516734.
17. Lee, Heng-Chi; Chang, Shwu-Shin; Choudhary, Swati; Aalto, Antti P.; Maiti, Mekhala; Bamford, Dennis H.; Liu, Yi (2009-05-14). "qiRNA is a new type of small interfering RNA induced by DNA damage". Nature. 459 (7244): 274–277. Bibcode:2009Natur.459..274L. doi:10.1038/nature08041. ISSN   1476-4687. PMC   2859615 . PMID   19444217.
18. Mochizuki, Kazufumi; Gorovsky, Martin A (April 2004). "Small RNAs in genome rearrangement in Tetrahymena" . Current Opinion in Genetics & Development. 14 (2): 181–187. doi:10.1016/j.gde.2004.01.004.
19. Silva, Jose M.; Li, Mamie Z.; Chang, Ken; Ge, Wei; Golding, Michael C.; Rickles, Richard J.; Siolas, Despina; Hu, Guang; Paddison, Patrick J.; Schlabach, Michael R.; Sheth, Nihar; Bradshaw, Jeff; Burchard, Julia; Kulkarni, Amit; Cavet, Guy (November 2005). "Second-generation shRNA libraries covering the mouse and human genomes" . Nature Genetics. 37 (11): 1281–1288. doi:10.1038/ng1650. ISSN   1546-1718. PMID   16200065.
20. Tiwari, Deepti; Patel, Manoj Kumar (May 7, 2024). "22 Nucleotide siRNAs: Emerging Players in Plant Stress Adaptation" (PDF). Biotica Research Today. 6 (5): 249–251.
21. Weinberg, Marc S.; Morris, Kevin V. (2016-08-19). "Transcriptional gene silencing in humans". Nucleic Acids Research. 44 (14): 6505–6517. doi:10.1093/nar/gkw139. ISSN   1362-4962. PMC   5001580 . PMID   27060137.
22. Valadkhan, Saba; Gunawardane, Lalith S. (2013-04-30). Lindsay, Mark A.; Griffiths-Jones, Sam (eds.). "Role of small nuclear RNAs in eukaryotic gene expression". Essays in Biochemistry. 54: 79–90. doi:10.1042/bse0540079. ISSN   0071-1365. PMC   11246792 . PMID   23829528.
23. Huang, Zheng-hao; Du, Yu-ping; Wen, Jing-tao; Lu, Bing-feng; Zhao, Yang (2022-05-12). "snoRNAs: functions and mechanisms in biological processes, and roles in tumor pathophysiology". Cell Death Discovery. 8 (1): 259. doi:10.1038/s41420-022-01056-8. ISSN   2058-7716. PMC   9098889 . PMID   35552378.
24. Wei, Haibin; Zhou, Ben; Zhang, Fang; Tu, Yanyang; Hu, Yanan; Zhang, Baoguo; Zhai, Qiwei (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 . ISSN   1932-6203. PMC   3572043 . PMID   23418607.
25. Rana, Tariq M. (January 2007). "Illuminating the silence: understanding the structure and function of small RNAs" . Nature Reviews Molecular Cell Biology. 8 (1): 23–36. doi:10.1038/nrm2085. ISSN   1471-0072.
26. Xie, Yaoyao; Yao, Lipeng; Yu, Xiuchong; Ruan, Yao; Li, Zhe; Guo, Junming (2020-06-30). "Action mechanisms and research methods of tRNA-derived small RNAs". Signal Transduction and Targeted Therapy. 5 (1): 109. doi:10.1038/s41392-020-00217-4. ISSN   2059-3635. PMC   7326991 . PMID   32606362.
27. 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 . PMC   4893054 . PMID   27095039.
28. Valkov, Nedyalka; Das, Saumya (2020). "Y RNAs: Biogenesis, Function and Implications for the Cardiovascular System". Non-coding RNAs in Cardiovascular Diseases. Advances in Experimental Medicine and Biology. Vol. 1229. pp. 327–342. doi:10.1007/978-981-15-1671-9_20. ISBN   978-981-15-1670-2. ISSN   0065-2598. PMC   7363058 . PMID   32285422.
29. 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 . PMC   8973356 . PMID   35354369.
30. Hewezi T (2020-08-25). "Epigenetic Mechanisms in Nematode–Plant Interactions". Annual Review of Phytopathology . 58 (1). Annual Reviews: 119–138. Bibcode:2020AnRvP..58..119H. doi:10.1146/annurev-phyto-010820-012805. ISSN   0066-4286. PMID   32413274. S2CID   218658491.