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Roles of Regulatory RNAs in Biology and Disease
The study of RNA has been a developing field over the past few decades. Whereas DNA is the information molecule that codes for everything in an organism, RNA is the vehicle for transformation from encoded information to a direct product. RNA can be coding and non-coding. Coding RNA, or messenger RNA, is the intermediary between DNA and protein synthesis. The non-coding RNA, including ribosomal RNA, transfer RNA, and regulatory RNA, supports the translation of the coded message and regulates the rate product output. Regulatory RNA includes small interfering RNA, microRNAs, PIWI-interacting RNAs, small nucleolar RNAs, small nuclear RNAs, and long noncoding RNAs. Because regulation is necessary for a wide variety of processes, regulatory RNAs are involved in many systems and diseases, like pathway activation and inactivation, organism development and differentiation, DNA repair, phylogeny, cancer, infectious disease, immunological disease, diagnostics, and toxicity. Regulatory RNAs are a huge focus for new research and therapies.
RNA is critical to a cell’s ability to form proteins as part of the central dogma. RNA is more flexible and unstable compared to DNA; it is often single-stranded or double-stranded, is prone to hydrolyzation thanks to a hydroxyl group on its 2’ carbon, and it can bind to itself, other RNAs, and DNA (7). RNA can either code for proteins or have a its own functionality as an RNA. Types of RNA include coding RNA, also known as messenger RNA, noncoding RNA, also known as ribosomal RNA, transfer RNA, and regulatory RNA. Regulatory RNAs are a subclass of noncoding RNAs that can still influence an organism’s genomic expression and control (5). If an RNA is complementary to another RNA and interferes with its function, it is considered an antisense RNA (1).
Figure 1: The types of RNA found in an organism. RNA can be broken down into coding and non-coding RNA. Coding RNA is referred to as messenger RNA. Non-coding RNA can be broken down into ribosomal RNA, transfer RNA, and regulatory RNA. Regulatory RNAs can be broken down into small interfering RNA, microRNAs, PIWI-interacting RNAs, small nucleolar RNAs, small nuclear RNAs, and long noncoding RNAs.
Types of Regulatory RNAs
According to a book written by Mallick and Ghosh, the main types of regulatory discovered so far are small interfering RNAs (siRNAs), microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), and long noncoding RNAs (lncRNAs) (5).
siRNA stands for small interfering RNAs, and like the name suggests, can bind to mRNA sequences and inhibit translation through a process called RNA interference, or RNAi (7). In RNA interference, an endonuclease that is part of the RNase III family called Dicer cleaves long double-stranded RNA into siRNA around 20 bases long, which can then combine with other proteins to induce RISCs, or RNA-induced silencing complexes (8).
Dicer is also involved in the generation of microRNAs, or miRNAs; miRNAs interact with messenger RNAs, usually in the 3’ untranslated region, to induce mRNA degradation or translation inhibition (7). miRNAs are a very common type of ncRNA, may regulate up to 30% of an organism’s gene expression, are typically around 22 bases in length, and may be encoded by up to 1% of an organism’s genome (7). Although miRNAs have 22 bases, they have a 5 base long region towards the 5’ region of the miRNA that is directly responsible for the recognition of a 3’ untranslated region (2). miRNAs are made by the following steps: first, the primary miRNA transcript binds to the proteins Drosha and Pasha, which processes them into 70-80 bases long hairpin sections (7) of pre-miRNAs, which then binds to exportin-5 to be carried out of the nucleus (6). Then, Dicer cleaves the pre-miRNA into 22 to 24 nucleotides-long segments of double stranded RNA (6). The double-stranded segments are unwound by RNA helicase (7) and the miRNA is incorporated into the argonaut (AGO) subunit of RISCs and become functional (6). Typically, microRNAs can be found in introns of genes or be expressed independently of other genes (2).
Figure 2: miRNA Synthesis; First, the primary miRNA is cleaved into pre-miRNA by Drosha and Pasha; then Exportin-5 transports the pre-miRNA through the nucleus into the cytoplasm. Next, Dicer cleaves the pre-miRNA into 22-24 nucleotide segments, helicase separates the double-stranded RNA into single-strands, and the miRNA binds to the AGO subunit of the RISC complex and becomes functional.
piRNAs, or PIWI-interacting RNAs, are the most recently discovered subsection of regulatory RNAs and were identified in 2006 (5). piRNAs bind to a subset of AGO proteins called PIWI proteins to specifically silence the expression of transposons in germ cells and protect against mutation (6). However, it also is found in brain and other tissues beyond germ cells, which suggests more functions than protecting offspring from genetic mutation (6).
Small nucleolar RNAs, or snoRNAs, are commonly found in other gene’s introns, are localized to the nucleolus in 60 to 100 base sequences, and are involved in nucleoside modification and cleavage reactions in mRNAs (7). snoRNAs bind to proteins to form complexes called snoRNPs; these complexes are either have a consensus box H/ACA or consensus box C/D, each of which help with pseudouridylylation and 2’-O-methylations, respectively (7).
Small nuclear RNA’s, or snRNAs, are involved in mRNA splicing and assembling the spliceosome (6). snRNAs U1 and U2 recognize the 5’ splice site and branch point, which allows U4, U5, and U6 to adhere to the site, displace U1, and guide the splice (6). snRNAs are typically between 100 and 200 nucleotides long (7).
Long non-coding RNAs, or lncRNAs, are a sort of catch-all grouping for regulatory enzymes that are longer than 200 bases long and are not a part of the aforementioned groups (6). Because of this, there is a lack of a cohesive singular purpose these regulatory RNAs perform, and there have been questions on the biological relevance of these RNAs (5). lncRNA are a upcoming research field for researchers interested in regulatory RNAs.
Most regulatory RNA is noncoding; however that does not mean that coding RNA is incapable of having regulatory functions. Some mRNAs may carry riboswitch sequences within them that can regulate translation by inducing different conformations in the mRNA in response to signals detected by the riboswitch region (4).
Obviously, the field of study regarding RNA regulation of the cell is still rapidly expanding, elucidating the intricacies of the human genome. As such, there may be unknown types of regulatory RNAs that scientists have yet to identify. Regulatory RNAs cover a diverse field of functions which makes them an important aspect to keep current with.
Because there is such a wide variety of regulatory RNAs, there is also a large variety in their respective functions. Examples of regulatory RNA functions can vary from development and differentiation, to epigenetic roles, to RNA modification, to evolution, and to inheritance (6).
The expression of regulatory RNAs may influence when specific genes are expressed or not expressed. For example, the expression of the lncRNA Braveheart triggers the expression of protein meSP1, which helps differentiate cardiovascular tissue during development (2). On the contrary, regulatory RNAs can inhibit expression of particular genes as well. The first microRNA, lin-4, was discovered in 1993 while studying C. elegans and inhibited the lin-14 gene by being antisense to several sites in the 3’ untranslated region of the lin-14 gene; the LIN-14 protein is only expressed in the first larval phase, and otherwise is kept unexpressed and degraded as an mRNA by the miRNA lin-4 (2).
Another function regulatory RNA can perform is the regulation of DNA repair mechanisms. microRNAs help regulate the base excision repair pathway through the expression of miRNA-16, miRNA-34c, miRNA-199a which regulates UNG2, an uracil-DNA glycosylase (9). miRNA-155, when overexpressed, inhibits hMSH2, hMSH6, and hMLH1, repressing mismatch repair pathways, which can help lead to an increase in mutagenesis (9). In nucleotide excision repair pathways, inhibition of RAD23B can occur with the overexpression of miRNA-373, leading to an increase in accumulation of UV induced damage (9).
Regulatory RNAs have significant roles in both prokaryotic and eukaryotic organisms. In S. aureus, antisense microRNAs bind to and regulate proteins controlling virulence (4). In strains with more antisense RNAs, there was a lower virulence (4). In bacteria, ncRNAs may regulate growth in response to stress as well; researchers have identified a set of ncRNAs, RsaA through K, which appear to help modulate metabolism and growth in S. aureus strains. Archaea have had ncRNA identified as well as homologous genes in the argonaut family, suggesting functional similarities to eukaryotes (10).
Regulatory RNAs have many functions during the development of an organism. Zebrafish generate miRNA-430 to bind to maternal mRNA immediately after the mid-blastula transition; miRNA-430 is nonspecific and recognizes about 40% of the maternal mRNA 3’ untranslated regions (2). Regulatory RNAs can influence overall cell processes, as seen with miRNA-1 and miRNA-133, which can influence the rate of cell division in cardiac muscle (2).
Regulatory RNA sequences can also provide phylogenetic evidence for evolution. Like conserved genes such as BMP Hox, Pax, and Wnt family genes, certain miRNAs are conserved across organisms as well, like miRNA-12 found in the gut cells of animals and miRNA-124 found in the central nervous systems of animals with nervous system differentiation (2).
Regulatory RNAs may regulate inflammation by inhibiting and activating certain pathways. miRNA-146a targets IRAK-1 and TRAF6 to affect the TLR signaling pathway (9). Following treatment with lipopolysaccharide, lung cells began to express miRNA-214, miRNA-21, miRNA-223, and miRNA-224 (9). In addition to influencing inflammation, regulatory RNAs are also responsible for controlling transcription factors responsible for T and B cell differentiation; for example, miRNA-150 targets c-myb in mature B cells but not immature B cells (9). siRNAs can be recognized by toll-like receptors like TLR3, TLR7, and TLR8 (11).
Roles in Disease
Overexpression of regulatory RNAs can result in disorders and disease. For example, when there is trisomy of chromosomes, such as with Down’s syndrome, there can be an increase in the expression of the microRNAs on the chromosome. As seen with the overexpression of miRNA-155, the increase in microRNA expression leads to the suppression of transcription factors necessary for neural and cardiac development (2). On the contrary, inhibition of the expression of regulatory RNAs seen in different diseases and disorders can pose a problem as well. In multiple myeloma cell lines, the expression of miRNA-342 and miRNA-363 is significantly lower than in healthy cell lines, and the protein it inhibits, Runx2, which promotes bone metastasis, is expressed at much higher levels (3). When the cells were transfected with miRNA-342 and miRNA-363 mimics, the expression of Runx2 was reduced (3). Targeting regulatory RNAs may be a tactical strategy for discovering new treatment pathways, especially in the area of cancer.
Researchers have been looking into the possibility or using miRNAs to differentiate tumor cells to remove some of their stem cell qualities (2). By increasing the expression of miRNAs that are considered tumor suppressors or methylation regulators, they hope to make the tumor cells have differentiated phenotypes so they are easier to treat (2). In addition, miRNAs can act directly as oncogenes and tumor suppressor genes. A cluster of 6 miRNAs, miRNA-17-92, is the direct target of oncogenic c-MYC transcription factors; additionally, it has been shown to be upregulated in lung, colon, pancreatic, prostate and breast cancers as well as lymphomas (9). When tumor-suppressive miRNAs are dysregulated, cancerous tissue can grow; when let7 is under expressed in cancer tissues, its target, the oncogene RAS, is able to be overexpressed (9).
Regulatory RNAs can be used as a diagnostic tool for disease. Studies have shown that specific changes in miRNA expression can be used to indicate the presence or absence of drug-induced liver toxicity (9). In rats, acetaminophen toxicity was shown to decrease miRNA-298 and miRNA-370 expression, both of which target oxidative-stress related enzymes, as soon as six hours after treatment with acetaminophen (9). It may be possible to use certain levels of miRNAs in the blood serum or urine associated with specific diseases as biomarkers; this is advantageous because miRNA meets the qualifications for a biomarker: high tissue specificity, availability, stability, detectable early, easy to measure, and associated with a known mechanism (9). miRNAs are highly tissue specific; miRNA-124 expression is quantifiable in brain tissues 270 to 24000-fold higher than in other tissues (9). Diseases can cause the release of miRNAs into the blood at different stages (9). miRNAs have been shown to be resistant to changes in pH and temperature, and they are easy to quantify using polymerase chain reaction (9).
Understanding regulatory RNAs can also be beneficial for public health and containing infections. Given that the binding of microRNAs to bacteria can affect the virulence of the bacteria, it may be possible to target the virulence of an infectious species to mitigate the harmful effects of the strain instead of trying to kill the pathogens (4).
Many immunological disorders can be influenced by regulatory RNAs as well. Disorders like rheumatoid arthritis, psoriasis, asthma, idiopathic pulmonary fibrosis, and inflammatory bowel disease have all been associated with irregularly upregulated or downregulated miRNAs. For example, in psoriasis, upregulation of miRNA-146a targets IRAK-1 and TRAF6 to stimulate the TNF-α pathway, which increases inflammation causing psoriasis (9).
Regulatory RNAs are a major portion of genomic regulation. Much of the research being done focuses on the impacts of microRNAs on different functions, however, siRNAs, piRNAs, snoRNAs, snRNAs, and lncRNAs all play important roles in the day to day function of cells in the body. Regulatory RNAs are involved with organism development, differentiation, DNA repair, bacterial virulence, phylogeny, cell processes, and pathway inhibition and activation.
Since there is such a diverse spread of functions, regulatory RNAs have a wide variety of implication in disease. miRNAs play an increasingly large role in regulating cancer in addition to affecting other diseases like immunological disorders. It can play a role in public health, diagnostics, and pathway regulation. Studying regulatory RNAs is integral to the future of scientific study and treatment, and it is important to keep current with the plethora of ongoing research being produced.
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- Gowda, P., Wildman, B., Trotter, T., Xu, X., Hao, X., Hassan, M., & Yang, Y. (2018). Runx2 suppression by miR-342 and miR-363 inhibits multiple myeloma progression. Molecular Cancer Research, 16(7), 1138-1148. doi:10.1158/1541-7786.MCR-17-0606
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