microRNA

ミクロRNA、マイクロRNA

関

miRNA

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/02/26 04:24:08」(JST)

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マイクロRNAは生物自身のDNAもしくはイントロンから合成される。

miRNA（micro-RNA）とは、細胞内に存在する長さ20から25塩基ほどの1本鎖RNAをいい、他の遺伝子の発現を調節する機能を有すると考えられているncRNA（ノンコーディングRNA：タンパク質への翻訳はされない）の一種である。

miRNAの元になるDNA配列はmiRNAより長く、miRNAの配列と、それにほぼ相補的な逆向きの配列とを含む。このDNA配列が1本鎖RNAに転写されると、miRNA配列とその逆相補配列は相補的に結合して2本鎖になり、全体としてはヘアピンループ構造（tRNAに似た形）をとる。これをprimary miRNA（pri-miRNA）という。通常、ヘアピンループ構造をとる部分以外にもミスマッチが含まれており、スターフォームとよばれる。核内にあるDroshaと呼ばれる酵素がこのpri-miRNA分子の一部を切断してpre-miRNA（ miRNAの直接の前駆体）を作る。次いでpre-miRNA分子はExportin-5と呼ばれるキャリアタンパク質によって核外に輸送され、これからダイサー（Dicer：RNAiを参照）により20-25塩基のmiRNA配列が切り出される（植物ではpri-miRNAが直接ダイサーによって処理される）。

miRNAの機能は遺伝子発現の抑制にあると思われる。miRNA は一部のmRNA（大抵は3'側非翻訳領域）に相補的な配列を有する。このmRNAとmiRNAとの結合により、翻訳が阻害される場合（下述のstRNA）、またRNAiのようにmRNAの分解を引き起こす場合があると考えられている。

このmiRNAの効果は1993年にR.C.LeeらによってC.elegansで初めて発見された（これはsmall temporal RNA＝stRNAと呼ばれた ）。その後miRNAはいろいろな植物（シロイヌナズナなど）や動物（C.elegansやヒトなど）で確認されている（Baulcombe 2002）。細菌にも、mRNAに結合してmRNA量や翻訳を調節する似たような遺伝子が発見されているが、ダイサーは関与しないので、一般にはmiRNAとは考えられていない。

miRNAの語はサイエンスの 3 報の論文（2001年10月26日、[1]）で提唱された。

植物では類似のRNAであるshort-interfering RNA（siRNA）がウイルスRNAの転写を阻止する機能を有し、また一部は細胞自身の遺伝子の調節にも関わっている。siRNAは2本鎖であるが、ヘアピンループ構造を有し、作用機構はmiRNAに近いと思われる。

miRNAの活性は、実験的には人工合成核酸であるモルホリノアンチセンスオリゴを用いて阻害できる。

参考文献

• miRNAの命名・分類についての指針： Victor Ambros, Bonnie Bartel, David P. Bartel, Christopher B. Burge, James C. Carrington, Xuemei Chenand, Gideon Dreyfuss, Sean R. Eddy, Sam Griffiths-Jones, Mhairi Marshall, Marjori Matzke, Gary Ruvkun and Thomas Tuschl (2003) "A uniform system for microRNA annotation", RNA, 9: 277-279. [2]

• miRNAとsiRNAが関与する過程の報告（サイエンスの同号の他2論文とともに）： DavidBaulcombe(2002)"AnRNAMicrocosm",Science,297:2002-2003.[3]

• miRNAとして初めて発見されたlin-4 の報告： Lee, R.C., Feinbaum, R.L. and Ambros, V. (1993) "The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14", Cell, 75: 843–854. [4] 。なおAmbros研究室からのmiRNAに関する論文は[5]を見よ。

外部リンク

• miRNAデータベース： miRBase

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Diagram of miRNA action with mRNA

The stem-loop secondary structure of a pre-microRNA from Brassica oleracea.

A microRNA (abbr. miRNA) is a small non-coding RNA molecule (ca. 22 nucleotides) found in plants and animals, which functions in transcriptional and post-transcriptional regulation of gene expression. Encoded by eukaryotic nuclear DNA, miRNAs function via base-pairing with complementary sequences within mRNA molecules, usually resulting in gene silencing via translational repression or target degradation. The human genome may encode over 1000 miRNAs, which may target about 60% of mammalian genes and are abundant in many human cell types.

miRNAs are well conserved in eukaryotic organisms and are thought to be a vital and evolutionarily ancient component of genetic regulation. While core components of the microRNA pathway are conserved between plants and animals, miRNA repertoires in the two kingdoms appear to have evolved independently with different modes of function. Plant miRNAs usually have perfect or near-perfect pairing with their messenger RNA targets and induce gene repression through degradation of their target transcripts. Plant miRNAs may bind their targets in both coding regions and untranslated regions. In contrast, animal miRNAs typically exhibit only partial complementarity to their mRNA targets. A 'seed region' of about 6-8 nucleotides in length at the 5' end of an animal miRNA is thought to be an important determinant of target specificity. Combinatorial regulation is a feature of miRNA regulation. A given miRNA may have multiple different mRNA targets, and a given target might similarly be targeted by multiple miRNAs.

The first miRNAs were characterized in the early 1990s. However, miRNAs were not recognized as a distinct class of biological regulators with conserved functions until the early 2000s. Since then, miRNA research has revealed multiple roles in negative regulation (transcript degradation and sequestering, translational suppression) and possible involvement in positive regulation (transcriptional and translational activation). By affecting gene regulation, miRNAs are likely to be involved in most biological processes. Different sets of expressed miRNAs are found in different cell types and tissues.

Aberrant expression of miRNAs has been implicated in numerous disease states, and miRNA-based therapies are under investigation.

History

MicroRNAs were discovered in 1993 by Victor Ambros, Rosalind Lee and Rhonda Feinbaum during a study of the gene lin-14 in C. elegans development. They found that LIN-14 protein abundance was regulated by a short RNA product encoded by the lin-4 gene. A 61-nucleotide precursor from the lin-4 gene matured to a 22-nucleotide RNA that contained sequences partially complementary to multiple sequences in the 3’ UTR of the lin-14 mRNA. This complementarity was both necessary and sufficient to inhibit the translation of the lin-14 mRNA into the LIN-14 protein. Retrospectively, the lin-4 small RNA was the first microRNA to be identified, though at the time, it was thought to be a nematode idiosyncrasy. Only in 2000 was a second RNA characterized: let-7, which repressed lin-41, lin-14, lin-28, lin-42, and daf-12 expression during developmental stage transitions in C. elegans. let-7 was soon found to be conserved in many species, indicating the existence of a wider phenomenon.

Nomenclature

Under a standard nomenclature system, names are assigned to experimentally confirmed miRNAs before publication of their discovery. The prefix "mir" is followed by a dash and a number, the latter often indicating order of naming. For example, mir-123 was named and likely discovered prior to mir-456. The uncapitalized "mir-" refers to the pre-miRNA, while a capitalized "miR-" refers to the mature form. miRNAs with nearly identical sequences except for one or two nucleotides are annotated with an additional lower case letter. For example, miR-123a would be closely related to miR-123b. Pre-miRNAs that lead to 100% identical mature miRNAs but that are located at different places in the genome are indicated with an additional dash-number suffix. For example, the pre-miRNAs hsa-mir-194-1 and hsa-mir-194-2 lead to an identical mature miRNA (hsa-miR-194) but are located in different regions of the genome. Species of origin is designated with a three-letter prefix, e.g., hsa-miR-123 is a human (Homo sapiens) miRNA and oar-miR-123 is a sheep (Ovis aries) miRNA. Other common prefixes include 'v' for viral (miRNA encoded by a viral genome) and 'd' for Drosophila miRNA (a fruit fly commonly studied in genetic research). When two mature microRNAs originate from opposite arms of the same pre-miRNA, they are denoted with a -3p or -5p suffix. (In the past, this distinction was also made with 's' (sense) and 'as' (antisense)). When relative expression levels are known, an asterisk following the name indicates an miRNA expressed at low levels relative to the miRNA in the opposite arm of a hairpin. For example, miR-123 and miR-123* would share a pre-miRNA hairpin, but more miR-123 would be found in the cell.

Biogenesis

MicroRNAs are produced from either their own genes or from introns. A video of this process can be found here.

The majority of the characterized miRNA genes are intergenic or oriented antisense to neighboring genes and are therefore suspected to be transcribed as independent units. However, in some cases a microRNA gene is transcribed together with its host gene; this provides a mean for coupled regulation of miRNA and protein-coding gene. As much as 40% of miRNA genes may lie in the introns of protein and non-protein coding genes or even in exons of long nonprotein-coding transcripts. These are usually, though not exclusively, found in a sense orientation, and thus usually are regulated together with their host genes. Other miRNA genes showing a common promoter include the 42-48% of all miRNAs originating from polycistronic units containing multiple discrete loops from which mature miRNAs are processed, although this does not necessarily mean the mature miRNAs of a family will be homologous in structure and function. The promoters mentioned have been shown to have some similarities in their motifs to promoters of other genes transcribed by RNA polymerase II such as protein coding genes. The DNA template is not the final word on mature miRNA production: 6% of human miRNAs show RNA editing (IsomiRs), the site-specific modification of RNA sequences to yield products different from those encoded by their DNA. This increases the diversity and scope of miRNA action beyond that implicated from the genome alone.

Transcription

miRNA genes are usually transcribed by RNA polymerase II (Pol II). The polymerase often binds to a promoter found near the DNA sequence encoding what will become the hairpin loop of the pre-miRNA. The resulting transcript is capped with a specially-modified nucleotide at the 5’ end, polyadenylated with multiple adenosines (a poly(A) tail), and spliced. Animal miRNAs are initially transcribed as part of one arm of an ∼80 nucleotide RNA stem-loop that in turn forms part of a several hundred nucleotides long miRNA precursor termed a primary miRNA (pri-miRNA)s. When a stem-loop precursor is found in the 3’ UTR, a transcript may serve as a pri-miRNA and a mRNA. RNA polymerase III (Pol III) transcribes some miRNAs, especially those with upstream Alu sequences, transfer RNAs (tRNAs), and mammalian wide interspersed repeat (MWIR) promoter units.

Nuclear processing

A single pri-miRNA may contain from one to six miRNA precursors. These hairpin loop structures are composed of about 70 nucleotides each. Each hairpin is flanked by sequences necessary for efficient processing. The double-stranded RNA structure of the hairpins in a pri-miRNA is recognized by a nuclear protein known as DiGeorge Syndrome Critical Region 8 (DGCR8 or "Pasha" in invertebrates), named for its association with DiGeorge Syndrome. DGCR8 associates with the enzyme Drosha, a protein that cuts RNA, to form the "Microprocessor" complex. In this complex, DGCR8 orients the catalytic RNase III domain of Drosha to liberate hairpins from pri-miRNAs by cleaving RNA about eleven nucleotides from the hairpin base (two helical RNA turns into the stem). The product resulting has a two-nucleotide overhang at its 3’ end; it has 3' hydroxyl and 5' phosphate groups. It is often termed as a pre-miRNA (precursor-miRNA).

pre-miRNAs that are spliced directly out of introns, bypassing the Microprocessor complex, are known as "Mirtrons." Originally thought to exist only in Drosophila and C. elegans, mirtrons have now been found in mammals.

Perhaps as many as 16% of pri-miRNAs may be altered through nuclear RNA editing. Most commonly, enzymes known as adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine (A to I) transitions. RNA editing can halt nuclear processing (for example, of pri-miR-142, leading to degradation by the ribonuclease Tudor-SN) and alter downstream processes including cytoplasmic miRNA processing and target specificity (e.g., by changing the seed region of miR-376 in the central nervous system).

Nuclear export

pre-miRNA hairpins are exported from the nucleus in a process involving the nucleocytoplasmic shuttle Exportin-5. This protein, a member of the karyopherin family, recognizes a two-nucleotide overhang left by the RNase III enzyme Drosha at the 3' end of the pre-miRNA hairpin. Exportin-5-mediated transport to the cytoplasm is energy-dependent, using GTP bound to the Ran protein.

Cytoplasmic processing

In cytoplasm, the pre-miRNA hairpin is cleaved by the RNase III enzyme Dicer. This endoribonuclease interacts with the 3' end of the hairpin and cuts away the loop joining the 3' and 5' arms, yielding an imperfect miRNA:miRNA* duplex about 22 nucleotides in length. Overall hairpin length and loop size influence the efficiency of Dicer processing, and the imperfect nature of the miRNA:miRNA* pairing also affects cleavage. Although either strand of the duplex may potentially act as a functional miRNA, only one strand is usually incorporated into the RNA-induced silencing complex (RISC) where the miRNA and its mRNA target interact.

Biogenesis in plants

miRNA biogenesis in plants differs from animal biogenesis mainly in the steps of nuclear processing and export. Instead of being cleaved by two different enzymes, once inside and once outside the nucleus, both cleavages of the plant miRNA is performed by a Dicer homolog, called Dicer-like1 (DL1). DL1 is only expressed in the nucleus of plant cells, which indicates that both reactions take place inside the nucleus. Before plant miRNA:miRNA* duplexes are transported out of the nucleus its 3' overhangs are methylated by a RNA methyltransferaseprotein called Hua-Enhancer1 (HEN1). The duplex is then transported out of the nucleus to the cytoplasm by a protein called Hasty (HST), an Exportin 5 homolog, where they disassemble and the mature miRNA is incorporated into the RISC.

The RNA-induced silencing complex

Main article: RNA-induced silencing complex

The mature miRNA is part of an active RNA-induced silencing complex (RISC) containing Dicer and many associated proteins. RISC is also known as a microRNA ribonucleoprotein complex (miRNP); RISC with incorporated miRNA is sometimes referred to as "miRISC."

Dicer processing of the pre-miRNA is thought to be coupled with unwinding of the duplex. Generally, only one strand is incorporated into the miRISC, selected on the basis of its thermodynamic instability and weaker base-pairing relative to the other strand. The position of the stem-loop may also influence strand choice. The other strand, called the passenger strand due to its lower levels in the steady state, is denoted with an asterisk (*) and is normally degraded. In some cases, both strands of the duplex are viable and become functional miRNA that target different mRNA populations.

Members of the Argonaute (Ago) protein family are central to RISC function. Argonautes are needed for miRNA-induced silencing and contain two conserved RNA binding domains: a PAZ domain that can bind the single stranded 3’ end of the mature miRNA and a PIWI domain that structurally resembles ribonuclease-H and functions to interact with the 5’ end of the guide strand. They bind the mature miRNA and orient it for interaction with a target mRNA. Some argonautes, for example human Ago2, cleave target transcripts directly; argonautes may also recruit additional proteins to achieve translational repression. The human genome encodes eight argonaute proteins divided by sequence similarities into two families: AGO (with four members present in all mammalian cells and called E1F2C/hAgo in humans), and PIWI (found in the germ line and hematopoietic stem cells).

Additional RISC components include TRBP [human immunodeficiency virus (HIV) transactivating response RNA (TAR) binding protein], PACT (protein activator of the interferon induced protein kinase (PACT), the SMN complex, fragile X mental retardation protein (FMRP), Tudor staphylococcal nuclease-domain-containing protein (Tudor-SN), the putative DNA helicase MOV10, and the RNA recognition motif containing protein TNRC6B.

Mode of silencing

Gene silencing may occur either via mRNA degradation or preventing mRNA from being translated. For example, miR16 contains a sequence complementary to the AU-rich element found in the 3'UTR of many unstable mRNAs, such as TNF alpha or GM-CSF (ref Jing, Q., et al. Cell 2005 pmid = 15766526). It has been demonstrated that if there is complete complementation between the miRNA and target mRNA sequence, Ago2 can cleave the mRNA and lead to direct mRNA degradation. Yet, if there isn't complete complementation the silencing is achieved by preventing translation.

miRNA turnover

Turnover of mature miRNA is needed for rapid changes in miRNA expression profiles. During miRNA maturation in the cytoplasm, uptake by the Argonaute protein is thought to stabilize the guide strand, while the opposite (* or "passenger") strand is preferentially destroyed. In what has been called a "Use it or lose it" strategy, Argonaute may preferentially retain miRNAs with many targets over miRNAs with few or no targets, leading to degradation of the non-targeting molecules.

Decay of mature miRNAs in Caenorhabditis elegans is mediated by the 5´-to-3´ exoribonuclease XRN2, also known as Rat1p. In plants, SDN (small RNA degrading nuclease) family members degrade miRNAs in the opposite (3'-to-5') direction. Similar enzymes are encoded in animal genomes, but their roles have not yet been described.

Several miRNA modifications affect miRNA stability. As indicated by work in the model organism Arabidopsis thaliana (thale cress), mature plant miRNAs appear to be stabilized by the addition of methyl moieties at the 3' end. The 2'-O-conjugated methyl groups block the addition of uracil (U) residues by uridyltransferase enzymes, a modification that may be associated with miRNA degradation. However, uridylation may also protect some miRNAs; the consequences of this modification are incompletely understood. Uridylation of some animal miRNAs has also been reported. Both plant and animal miRNAs may be altered by addition of adenine (A) residues to the 3' end of the miRNA. An extra A added to the end of mammalian miR-122, a liver-enriched miRNA important in Hepatitis C, stabilizes the molecule, and plant miRNAs ending with an adenine residue have slower decay rates.

Cellular functions

Interaction of microRNA with protein translation process. Several (from nine documented) mechanisms of translation repression are shown: M1) on the initiation process, preventing assembling of the initiation complex or recruiting the 40S ribosomal subunit; M2) on the ribosome assembly; M3) on the translation process; M7, M8) on the degradation of mRNA. There exist other mechanisms of microRNA action on protein translation (transcriptional, transport to P-bodies, ribosome drop-off, co-translational protein degradation and others) that are not visualized here. Here, 40S and 60S are light and heavy components of the ribosome, 80S is the assembled ribosome bound to mRNA, eIF4F is an translation initiation factor, PABC1 is the Poly-A binding protein, and "cap" is the mRNA cap structure needed for mRNA circularization (which can be the normal m7G-cap or artificial modified A-cap). The initiation of mRNA can proceed in a cap-independent manner, through recruiting 40S to IRES (Internal Ribosome Entry Site) located in 5’UTR region. The actual work of RNA silencing is performed by RISC (RNA-induced silencing complex) in which the main catalytic subunit is one of the Argonaute proteins (AGO), and miRNA serves as a template for recognizing specific mRNA sequences.

The function of miRNAs appears to be in gene regulation. For that purpose, a miRNA is complementary to a part of one or more messenger RNAs (mRNAs). Animal miRNAs are usually complementary to a site in the 3' UTR whereas plant miRNAs are usually complementary to coding regions of mRNAs. Perfect or near perfect base pairing with the target RNA promotes cleavage of the RNA. This is the primary mode of plant miRNAs. In animals miRNAs more often have only partly the right sequence of nucleotides to bond with the target mRNA. The match-ups are imperfect. For partially complementary microRNAs to recognise their targets, nucleotides 2–7 of the miRNA (its 'seed region') still have to be perfectly complementary. Animal miRNAs inhibit protein translation of the target mRNA (this exists in plants as well but is less common). MicroRNAs that are partially complementary to a target can also speed up deadenylation, causing mRNAs to be degraded sooner. While degradation of miRNA-targeted mRNA is well documented, whether or not translational repression is accomplished through mRNA degradation, translational inhibition, or a combination of the two is hotly debated. Recent work on miR-430 shows that translational repression is caused by the disruption of translation initiation, independent of mRNA deadenylation.

miRNAs occasionally also cause histone modification and DNA methylation of promoter sites, which affects the expression of target genes.

Nine mechanisms of miRNA action are described and assembled in a unified mathematical model:

1. Cap-40S initiation inhibition;
2. 60S Ribosomal unit joining inhibition;
3. Elongation inhibition;
4. Ribosome drop-off (premature termination);
5. Co-translational nascent protein degradation;
6. Sequestration in P-bodies;
7. mRNA Decay (destabilisation);
8. mRNA Cleavage;
9. Transcriptional inhibition through microRNA-mediated chromatin reorganization following by gene silencing.

It is often impossible to discern these mechanisms using the experimental data about stationary reaction rates. Nevertheless, they are differentiated in dynamics and have different kinetic signatures.

Unlike plant microRNAs, the animal microRNAs target a diverse set of genes. However, genes involved in functions common to all cells, such as gene expression, have relatively fewer microRNA target sites and seem to be under selection to avoid targeting by microRNAs.

dsRNA can also activate gene expression, a mechanism that has been termed "small RNA-induced gene activation" or RNAa. dsRNAs targeting gene promoters can induce potent transcriptional activation of associated genes. This was demonstrated in human cells using synthetic dsRNAs termed small activating RNAs (saRNAs), but has also been demonstrated for endogenous microRNA.

Interactions between microRNAs and complementary sequences on genes and even pseudogenes that share sequence homology are thought to be a back channel of communication regulating expression levels between paralogous genes. Given the name "competing endogenous RNAs" (ceRNAs), these microRNAs bind to "microRNA response elements" on genes and pseudogenes and may provide another explanation for the persistence of non-coding DNA.

Evolution

MicroRNAs are significant phylogenetic markers because of their astonishingly low rate of evolution. Their origin may have permitted the development of morphological innovation, and by making gene expression more specific and 'fine-tunable', permitted the genesis of complex organs and perhaps, ultimately, complex life. Indeed, rapid bursts of morphological innovation are generally associated with a high rate of microRNA accumulation.

MicroRNAs originate predominantly by the random formation of hairpins in "non-coding" sections of DNA (i.e. introns or intergene regions), but also by the duplication and modification of existing microRNAs. The rate of evolution (i.e. nucleotide substitution) in recently-originated microRNAs is comparable to that elsewhere in the non-coding DNA, implying evolution by neutral drift; however, older microRNAs have a much lower rate of change (often less than one substitution per hundred million years), suggesting that once a microRNA gains a function it undergoes extreme purifying selection. At this point, a microRNA is rarely lost from an animal's genome, although microRNAs which are more recently derived (and thus presumably non-functional) are frequently lost. This makes them a valuable phylogenetic marker, and they are being looked upon as a possible solution to such outstanding phylogenetic problems as the relationships of arthropods.

MicroRNAs feature in the genomes of most eukaryotic organisms, from the brown algae to the animals. Across all species, in excess of 5000 had been identified by March 2010. Whilst short RNA sequences (50 – hundreds of base pairs) of a broadly comparable function occur in bacteria, bacteria lack true microRNAs.

Experimental detection and manipulation of miRNA

While researchers have focused on the study of miRNA expression in physiological and pathological processes, various technical variables related to microRNA isolation have emerged. The stability of the stored miRNA samples has often been questioned. MicroRNAs are degraded much more easily than mRNAs, partly due to their length, but also because of the ubiquitously present RNases. This makes it necessary to cool samples on ice and use RNase-free equipment whenever working with microRNAs.

MicroRNA expression can be quantified in a two-step polymerase chain reaction process of modified RT-PCR followed by quantitative real-time PCR. Variations of this method achieve absolute or relative quantification. miRNAs can also be hybridized to microarrays, slides or chips with probes to hundreds or thousands of miRNA targets, so that relative levels of miRNAs can be determined in different samples. MicroRNAs can be both discovered and profiled by high-throughput sequencing methods (MicroRNA Sequencing). The activity of an miRNA can be experimentally inhibited using a locked nucleic acid (LNA) oligo, a Morpholino oligo or a 2'-O-methyl RNA oligo. Additionally, a specific miRNA can be silenced by a complementary antagomir. MicroRNA maturation can be inhibited at several points by steric-blocking oligos. The miRNA target site of an mRNA transcript can also be blocked by a steric-blocking oligo. For the “in situ” detection of miRNA, LNA or Morpholino probes can be used. The locked conformation of LNA results in enhanced hybridization properties and increases sensitivity and selectivity, making it ideal for detection of short miRNA.

High-throughput quantification of miRNAs is often difficult and prone to errors, for the larger variance (compared to mRNAs) that comes with the methodological problems. mRNA-expression is therefore often analyzed as well to check for miRNA-effects in their levels (e. g. in ). To pair mRNA- and miRNA-data, databases can be used which predict miRNA-targets based on their base sequence. While this is usually done after miRNAs of interest have been detected (e. g. because of high expression levels), ideas for analysis tools that integrate mRNA- and miRNA-expression information have been proposed.

miRNA and disease

Just as miRNA is involved in the normal functioning of eukaryotic cells, so has dysregulation of miRNA been associated with disease. A manually curated, publicly available database, miR2Disease, documents known relationships between miRNA dysregulation and human disease.

miRNA and inherited diseases

A mutation in the seed region of miR-96 causes hereditary progressive hearing loss. A mutation in the seed region of miR-184 causes hereditary keratoconus with anterior polar cataract. Deletion of the miR-17~92 cluster causes skeletal and growth defects.

miRNA and cancer

Role of miRNA in a cancer cell

Several miRNAs have been found to have links with some types of cancer and are sometimes referred to as "oncomirs." MicroRNA-21 was one of the first microRNAs to be identified as an oncomir.

A study of mice altered to produce excess c-Myc — a protein with mutated forms implicated in several cancers — shows that miRNA has an effect on the development of cancer. Mice that were engineered to produce a surplus of types of miRNA found in lymphoma cells developed the disease within 50 days and died two weeks later. In contrast, mice without the surplus miRNA lived over 100 days. Leukemia can be caused by the insertion of a viral genome next to the 17-92 array of microRNAs leading to increased expression of this microRNA.

Another study found that two types of miRNA inhibit the E2F1 protein, which regulates cell proliferation. miRNA appears to bind to messenger RNA before it can be translated to proteins that switch genes on and off.

By measuring activity among 217 genes encoding miRNA, patterns of gene activity that can distinguish types of cancers can be discerned. miRNA signatures may enable classification of cancer. This will allow doctors to determine the original tissue type which spawned a cancer and to be able to target a treatment course based on the original tissue type. miRNA profiling has already been able to determine whether patients with chronic lymphocytic leukemia had slow growing or aggressive forms of the cancer.

Transgenic mice that over-express or lack specific miRNAs have provided insight into the role of small RNAs in various malignancies. Much work has also been done on the role of microRNAs in establishing and maintaining cancer stem cells that are especially resistant to chemotherapy and often responsible for relapse.

A novel miRNA-profiling based screening assay for the detection of early-stage colorectal cancer has been developed and is currently in clinical trials. Early results showed that blood plasma samples collected from patients with early, resectable (Stage II) colorectal cancer could be distinguished from those of sex-and age-matched healthy volunteers. Sufficient selectivity and specificity could be achieved using small (less than 1 mL) samples of blood. The test has potential to be a cost-effective, non-invasive way to identify at-risk patients who should undergo colonoscopy.

Another role for miRNA in cancers is to use their expression level as a prognostic, for example one study on NSCLC samples found that low miR-324a levels could serve as a prognostic indicator of poor survival, another found that either high miR-185 or low miR-133b levels correlated with metastasis and poor survival in colorectal cancer.

Recent studies have miR-205 targeted for inhibiting the metastatic nature of breast cancer. Five members of the microRNA-200 family (miR-200a, miR-200b, miR-200c, miR-141 and miR-429) are down regulated in tumour progression of breast cancer.

miRNA and heart disease

The global role of miRNA function in the heart has been addressed by conditionally inhibiting miRNA maturation in the murine heart, and has revealed that miRNAs play an essential role during its development. miRNA expression profiling studies demonstrate that expression levels of specific miRNAs change in diseased human hearts, pointing to their involvement in cardiomyopathies. Furthermore, studies on specific miRNAs in animal models have identified distinct roles for miRNAs both during heart development and under pathological conditions, including the regulation of key factors important for cardiogenesis, the hypertrophic growth response, and cardiac conductance. miRNAs that regulate Leptin, peroxisome proliferator-activated receptor gamma, and CCAAT/enhancer binding protein-alpha mRNA expression, are inversely associated with cardiovascular risk factors.

miRNA and the nervous system

miRNAs appear to regulate the nervous system. Neural miRNAs are involved at various stages of synaptic development, including dendritogenesis (involving miR-132, miR-134 and miR-124), synapse formation and synapse maturation (where miR-134 and miR-138 are thought to be involved). Some studies find altered miRNA expression in schizophrenia.

miRNA and obesity

miRNAs play crucial roles in the regulation of stem cell progenitors differentiating into adipocytes. Studies to determine what role pluripotent stem cells play in adipogenesis, were examined in the immortalized human bone marrow-derived stromal cell line hMSC-Tert20. Decreased expression of miR-155,miR-221,and miR-222, have been found during the adipogenic programming of both immortalized and primary hMSCs, suggesting that they act as negative regulators of differentiation. Conversely, ectopic expression of the miRNAs 155,221, and 222 significantly inhibited adipogenesis and repressed induction of the master regulators PPARγ and CCAAT/enhancer-binding protein alpha (CEBPA). This paves the way for possible obesity treatments on the genetic level.

Another class of miRNAs that regulate insulin resistance, obesity, and diabetes, is the let-7 family. Let-7 is known to accumulate in human tissues during the course of aging. When let-7 was ectopically overexpressed to mimic accelerated aging, mice became insulin-resistant, and thus more prone to high fat diet-induced obesity and diabetes. In contrast when let-7 was inhibited by injections of let-7-specific antagomirs, mice become more insulin-sensitive, and remarkably resistant to high fat diet-induced obesity and diabetes. Not only could let-7 inhibition prevent obesity and diabetes, it could also reverse and cure diabetes. These experimental findings suggest that let-7 inhibition could represent a new therapy for obesity and type 2 diabetes.

miRNA and non-coding RNAs

When the human genome project mapped its first chromosome in 1999, it was predicted the genome would contain over 100,000 protein coding genes. However, only around 20,000 were eventually identified (International Human Genome Sequencing Consortium, 2004). Since then, the advent of bioinformatics approaches combined with genome tiling studies examining the transcriptome, systematic sequencing of full length cDNA libraries, and experimental validation (including the creation of miRNA derived antisense oligonucleotides called antagomirs) have revealed that many transcripts are non protein-coding RNA, including several snoRNAs and miRNAs.

miRNA and viruses

The expression of transcription activators by human herpesvirus-6 DNA is believed to be regulated by viral miRNA.

See also

• Gene expression
• RNAi
• siRNA
• List of miRNA target prediction tools
• List of miRNA gene prediction tools
• Small nucleolar RNA derived microRNA

References

Further reading

• Specific role of microRNAs in cancer stem cells: Jun Qian, Vinayakumar Siragam, Jiang Lin, Jichun Ma, Zhaoqun Deng (2011). "The role of microRNAs in the formation of cancer stem cells: Future directions for miRNAs". Hypothesis 9 (1): e10. http://www.hypothesisjournal.com/?p=1006.
• Role of microRNAs in viral oncogenesis: Scaria V, Jadhav V (2007). "microRNAs in viral oncogenesis". Retrovirology 4: 82. doi:10.1186/1742-4690-4-82. PMC 2217556. PMID 18036240. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2217556/.
• Role of microRNAs in Host-virus interactions: Scaria V; Hariharan, M; Maiti, S; Pillai, B; Brahmachari, SK (2006). "Host-Virus Interaction: A new role for microRNAs". Retrovirology 3 (1): 68. doi:10.1186/1742-4690-3-68. PMC 1626483. PMID 17032463. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1626483/.
• Defines miRNA and proposes guidelines to follow in classifying RNA genes as miRNA: Ambros V, Bartel B, Bartel DP, Burge CB, Carrington JC, Chen X, Dreyfuss G, Eddy SR, Griffiths-Jones S, Marshall M, Matzke M, Ruvkun G, Tuschl T (2003). "A uniform system for microRNA annotation". RNA 9 (3): 277–279. doi:10.1261/rna.2183803. PMC 1370393. PMID 12592000. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1370393/.
• Processes that miRNA and siRNAs are involved in: Baulcombe D (2002). "DNA events. An RNA microcosm". Science 297 (5589): 2002–2003. doi:10.1126/science.1077906. PMID 12242426.
• Discovery of lin-4, the first miRNA to be discovered: Lee RC, Feinbaum RL, Ambros V (1993). "The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14". Cell 75 (5): 843–854. doi:10.1016/0092-8674(93)90529-Y. PMID 8252621.
• Over-expression of a miRNA in mice leads to cancer Costinean S, Zanesi N, Pekarsky Y, Tili E, Volinia S, Heerema N, Croce CM (May 2006). "Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice". Proc. Natl. Acad. Sci. U.S.A. 103 (18): 7024–9. Bibcode 2006PNAS..103.7024C. doi:10.1073/pnas.0602266103. PMC 1459012. PMID 16641092. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1459012/.
• Role of microRNAs in skin: Sand M, Gambichler T, Sand D, Skrygan M, Altmeyer P, Bechara FG (2009). "MicroRNAs and the skin: tiny players in the body's largest organ". J Dermatol Sci 53 (3): 169–175. doi:10.1016/j.jdermsci.2008.10.004. PMID 19058951. http://www.laboratoriosilesia.com/upfiles/sibi/d_014_micrornas.pdf.

External links

• The miRBase database
• The miRNA Blog
• miR2Disease, a manually curated database documenting known relationships between miRNA dysregulation and human disease.
• semirna, Web application to search for microRNAs in a plant genome.
• miRandola: Extracellular Circulating microRNAs Database.

UpToDate Contents

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• 1. 臨床腫瘍学における遺伝子発現プロファイリング、プロテオミクス、およびマイクロRNAプロファイリングの概要 overview of gene expression profiling proteomics and microrna profiling in clinical oncology
• 2. 遺伝学およびゲノミクスのためのツール：遺伝子発現プロファイリング tools for genetics and genomics gene expression profiling
• 3. 炎症性ミオパチーの病因 pathogenesis of inflammatory myopathies
• 4. 切除可能な肝細胞癌のマネージメント：予後、術前補助化学療法と補助化学療法の役割、および治療後サーベイランス management of potentially resectable hepatocellular carcinoma prognosis role of neoadjuvant and adjuvant therapy and posttreatment surveillance
• 5. びまん性大細胞型B細胞性リンパ腫の予後 prognosis of diffuse large b cell lymphoma

English Journal

• Novel Polymorphisms in Porcine 3'UTR of the Leptin Gene, Including a Rare Variant within Target Sequence for MIR-9 Gene in Duroc Breed, not Associated with Production Traits.

• Mankowska M1, Szydlowski M, Salamon S, Bartz M, Switonski M.
• Animal biotechnology.Anim Biotechnol.2015 Apr 3;26(2):156-63. doi: 10.1080/10495398.2014.958612.
• The leptin gene (LEP) is considered as a functional candidate for production traits in livestock due to its crucial role in energy homeostasis. Because polymorphisms in regulatory sequences may affect gene expression, we searched for them in the 3'UTR of LEP and analyzed their association with produ
• PMID 25380469

• Role of microRNAs in cancers of the female reproductive tract: insights from recent clinical and experimental discovery studies.

• Logan M, Hawkins SM.
• Clinical science (London, England : 1979).Clin Sci (Lond).2015 Feb 1;128(3):153-80. doi: 10.1042/CS20140087.
• microRNAs (miRNAs) are small RNA molecules that represent the top of the pyramid of many tumorigenesis cascade pathways as they have the ability to affect multiple, intricate, and still undiscovered downstream targets. Understanding how miRNA molecules serve as master regulators in these important n
• PMID 25294164

• Selective microRNA uridylation by Zcchc6 (TUT7) and Zcchc11 (TUT4).

• Thornton JE1, Du P1, Jing L1, Sjekloca L2, Lin S1, Grossi E1, Sliz P3, Zon LI4, Gregory RI5.
• Nucleic acids research.Nucleic Acids Res.2015 Feb 1;42(18):11777-91. doi: 10.1093/nar/gku805. Epub 2014 Sep 15.
• Recent small RNA sequencing data has uncovered 3' end modification of mature microRNAs (miRNAs). This non-templated nucleotide addition can impact miRNA gene regulatory networks through the control of miRNA stability or by interfering with the repression of target mRNAs. The miRNA modifying enzymes
• PMID 25223788

Japanese Journal

• Effects of Decitabine on Invasion and Exosomal Expression of miR-200c and miR-141 in Oxaliplatin-Resistant Colorectal Cancer Cells

• Tanaka Shota,Hosokawa Mika,Ueda Kumiko [他]
• Biological & pharmaceutical bulletin 38(9), 1272-1279, 2015-09
• NAID 40020570672

• 母体血漿中胎盤特異的microRNA流入量と陣痛との関連 (特集 胎盤のバイオマーカー)

• 三浦 清徳,森崎 慎太郎,増﨑 英明
• 産科と婦人科 82(9), 1017-1023, 2015-09
• NAID 40020568068

• 胎盤由来microRNA : 妊娠高血圧症候群との関連 (特集 胎盤のバイオマーカー)

• 瀧澤 俊広,大口 昭英,Naing Banyar Than
• 産科と婦人科 82(9), 1011-1016, 2015-09
• NAID 40020568053

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