NamiRNAs

Last updated June 18, 2024

NamiRNAs are a type of miRNAs present in the nucleus, which can activate gene expression by binding to the enhancer, and therefore were named nuclear activating miRNAs (NamiRNAs), such as miR-24-1 and miR-26.^[1] These miRNAs loci are enriched with epigenetic markers that display enhancer activity like histone H3K27ac, P300/CBP, and DNaseI high-sensitivity loci. These NamiRNAs are able to activate the related enhancers and co-work with them to up-regulate the expression of neighboring genes. NamiRNAs are able to promote global gene transcription by binding their targeted enhancers in whole genome level.

Canonically, miRNAs silence gene expression through binding to the complementary sequences of their targeted mRNAs that are often located in the 3’UTR in the cytoplasm since the first miRNA lin-4 has been found by Ambros Victor.^[2] As so far, most studies of miRNAs have focused on those in the cytoplasm.

Other than the classical theory that miRNAs down-regulate target genes by binding to the 3’UTR of mRNA, it has also been shown that miRNAs could upregulate gene expression in certain cases, just like RNAa phenomenon, which describes a picture that miRNAs can bind to the promoter of the target genes to facilitate gene transcriptions.^[3] Moreover, Vasudevan S. et al. held that miRNAs display a pattern of up-regulation on gene transcription together with AGO2 and FXR1.^[4] The discovery of NamiRNAs showcases a complementary regulatory mechanism of miRNAs, demonstrating their different roles in the nucleus and cytoplasm.^[1]

Molecular mechanism

The classical theory of miRNAs is that genomic DNA first transcribes into pri-miRNAs. Next, pri-miRNAs were cleaved into pre-miRNAs by Drosha in the nucleus. Then, pre-miRNAs are transported into the cytoplasm via Exportin5, and are cut again by Dicer to form mature miRNAs. However, this theory cannot explain the distribution of miRNAs in the nucleus. One possible explanation is that miRNAs in cytoplasm can be carried back into the nucleus by some transport proteins. However, there is no direct evidence to support it. Another reasonable explanation is that pre-miRNAs could form mature miRNAs directly in the nucleus by Dicer cleavage.^[5] This is a simpler and more energy-efficient method. Yet, the molecular mechanism of NamiRNAs is still not fully understood.^{[ citation needed ]}

NamiRNA is overlapped within the enhancer regions and it is also activated when it positively regulates its corresponding enhancers.^[5] Thus, the crosstalk between NamiRNA and enhancer will further promote a series of genes transcription. We can say that NamiRNA and enhancer mutually affect each other to form a positive feedback network and together play regulatory functions on gene expression.^{[ citation needed ]}

Functions

NamiRNAs could interact with the corresponding enhancer, enhance the enrichment of active enhancer markers like H3K27ac and H3K4me1, and change chromatin status within the enhancer regions, thus promoting the cognate gene transcription at genome-wide scale.^{[ citation needed ]}

Perspectives on the role

Traditional theory holds that miRNAs play inhibitory functions in the cytoplasm by binding the 3’ UTR of targeted mRNA and downregulate gene transcription. The discovery of NamiRNAs provides a brand-new idea that miRNAs can also play positive roles on gene expression in transcriptional level in the nucleus. To summarize, miRNAs have dual functions in gene regulation in the cytoplasm and the nucleus. That is, miRNAs play an inhibitory function in the cytoplasm and an activating function for the gene expression in the nucleus, respectively. Meanwhile, a functional network between NamiRNAs and enhancers is put forward to illustrate their roles for the positive regulation of their targeted gene transcription. NamiRNA enhancer target gene activation network demonstrates the new function of miRNA located in the nucleus.^{[ citation needed ]}

Related Research Articles

<span class="mw-page-title-main">Messenger RNA</span> RNA that is read by the ribosome to produce a protein

In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.

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 silence said mRNA molecules by one or more of the following processes:

Cleavage of the mRNA strand into two pieces,
Destabilization of the mRNA by shortening its poly(A) tail, or
Reducing translation of the mRNA into proteins.

<span class="mw-page-title-main">Gene expression</span> Conversion of a genes sequence into a mature gene product or products

Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, and ultimately affect a phenotype. These products are often proteins, but in non-protein-coding genes such as transfer RNA (tRNA) and small nuclear RNA (snRNA), the product is a functional non-coding RNA. The process of gene expression is used by all known life—eukaryotes, prokaryotes, and utilized by viruses—to generate the macromolecular machinery for life.

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins produce messenger RNA (mRNA). Other segments of DNA are transcribed into RNA molecules called non-coding RNAs (ncRNAs).

In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.

Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products. Sophisticated programs of gene expression are widely observed in biology, for example to trigger developmental pathways, respond to environmental stimuli, or adapt to new food sources. Virtually any step of gene expression can be modulated, from transcriptional initiation, to RNA processing, and to the post-translational modification of a protein. Often, one gene regulator controls another, and so on, in a gene regulatory network.

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.

Small temporal RNA regulates gene expression during roundworm development by preventing the mRNAs they bind from being translated. In contrast to siRNA, stRNAs downregulate expression of target RNAs after translation initiation without affecting mRNA stability. Nowadays, stRNAs are better known as miRNAs.

mir-133 is a type of non-coding RNA called a microRNA that was first experimentally characterised in mice. Homologues have since been discovered in several other species including invertebrates such as the fruitfly Drosophila melanogaster. Each species often encodes multiple microRNAs with identical or similar mature sequence. For example, in the human genome there are three known miR-133 genes: miR-133a-1, miR-133a-2 and miR-133b found on chromosomes 18, 20 and 6 respectively. The mature sequence is excised from the 3' arm of the hairpin. miR-133 is expressed in muscle tissue and appears to repress the expression of non-muscle genes.

There are 89 known sequences today in the microRNA 19 (miR-19) family but it will change quickly. They are found in a large number of vertebrate species. The miR-19 microRNA precursor is a small non-coding RNA molecule that regulates gene expression. Within the human and mouse genome there are three copies of this microRNA that are processed from multiple predicted precursor hairpins:

mir-1 microRNA precursor family Type of RNA

The miR-1 microRNA precursor is a small micro RNA that regulates its target protein's expression in the cell. microRNAs are transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give products at ~22 nucleotides. In this case the mature sequence comes from the 3' arm of the precursor. The mature products are thought to have regulatory roles through complementarity to mRNA. In humans there are two distinct microRNAs that share an identical mature sequence, and these are called miR-1-1 and miR-1-2.

Post-transcriptional regulation is the control of gene expression at the RNA level. It occurs once the RNA polymerase has been attached to the gene's promoter and is synthesizing the nucleotide sequence. Therefore, as the name indicates, it occurs between the transcription phase and the translation phase of gene expression. These controls are critical for the regulation of many genes across human tissues. It also plays a big role in cell physiology, being implicated in pathologies such as cancer and neurodegenerative diseases.

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.

MiR-155 is a microRNA that in humans is encoded by the MIR155 host gene or MIR155HG. MiR-155 plays a role in various physiological and pathological processes. Exogenous molecular control in vivo of miR-155 expression may inhibit malignant growth, viral infections, and enhance the progression of cardiovascular diseases.

In molecular biology mir-126 is a short non-coding RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several pre- and post-transcription mechanisms.

In molecular biology miR-132 microRNA is a short non-coding RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms, generally reducing protein levels through the cleavage of mRNAs or the repression of their translation. Several targets for miR-132 have been described, including mediators of neurological development, synaptic transmission, inflammation and angiogenesis.

In molecular biology miR-205 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms. They are involved in numerous cellular processes, including development, proliferation, and apoptosis. Currently, it is believed that miRNAs elicit their effect by silencing the expression of target genes.

In molecular biology, competing endogenous RNAs regulate other RNA transcripts by competing for shared microRNAs (miRNAs). Models for ceRNA regulation describe how changes in the expression of one or multiple miRNA targets alter the number of unbound miRNAs and lead to observable changes in miRNA activity - i.e., the abundance of other miRNA targets. Models of ceRNA regulation differ greatly. Some describe the kinetics of target-miRNA-target interactions, where changes in the expression of one target species sequester one miRNA species and lead to changes in the dysregulation of the other target species. Others attempt to model more realistic cellular scenarios, where multiple RNA targets are affecting multiple miRNAs and where each target pair is co-regulated by multiple miRNA species. Some models focus on mRNA 3' UTRs as targets, and others consider long non-coding RNA targets as well. It's evident that our molecular-biochemical understanding of ceRNA regulation remains incomplete.

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References

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↑ Lee RC, Feinbaum RL, Ambros V (December 1993). "The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14". Cell. 75 (5): 843–54. doi: 10.1016/0092-8674(93)90529-Y . PMID 8252621.
↑ Place RF, Li LC, Pookot D, Noonan EJ, Dahiya R (February 2008). "MicroRNA-373 induces expression of genes with complementary promoter sequences". Proceedings of the National Academy of Sciences of the United States of America. 105 (5): 1608–13. Bibcode:2008PNAS..105.1608P. doi: 10.1073/pnas.0707594105 . JSTOR 25451330. PMC 2234192 . PMID 18227514. (Erratum: doi:10.1073/pnas.1803343115, PMID 29555737, Retraction Watch . If the erratum has been checked and does not affect the cited material, please replace {{ erratum |...}} with {{ erratum |...|checked=yes}}.)
↑ Vasudevan S, Tong Y, Steitz JA (December 2007). "Switching from repression to activation: microRNAs can up-regulate translation". Science. 318 (5858): 1931–4. Bibcode:2007Sci...318.1931V. doi:10.1126/science.1149460. PMID 18048652. S2CID 6173875.
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