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MicroRNA（miRNA）是一类内生的、长度约20-24个核苷酸的小RNA,是发夹结构的约70-90个碱基大小的单链RNA前体经过Dicer酶加工后生成。其在细胞内具有多种重要的调节作用。每个miRNA可以有多个靶基因，而几个miRNAs也可以调节同一个基因。这种复杂的调节网络既可以通过一个miRNA来调控多个基因的表达，也可以通过几个miRNAs的组合来精细调控某个基因的表达。随着miRNA调控基因表达的研究的逐步深入，将帮助我们理解高等真核生物的基因组的复杂性和复杂的基因表达调控网络。miRNA广泛存在于真核生物中，是一组不编码蛋白质的短序列RNA，其本身不具有开放阅读框（ORF）。成熟的miRNA，5′端有一个磷酸基团，3′端为羟基。编码miRNAs的基因最初产生一个长的pri-RNA分子，这种初期分子还必须被剪切成约70-90个碱基大小、具发夹结构单链RNA前体（pre-miRNA）并经过Dicer酶加工后生成。成熟的miRNA 5’端的磷酸基团和3´端羟基则是它与相同长度的功能RNA降解片段的区分标志。miRNA 5＇端第一个碱基对U（尿苷）有强烈的倾向性，而对G却排斥，但第二到第四个碱基缺乏U。一般来讲，除第四个碱基外，其他位置碱基通常都缺乏C。这些分子能够与那些和它的序列互补的mRNA分子相结合，有时候甚至可以与特定的DNA片断结合。这种结合的结果就是导致基因的沉默。这种方式是身体调节基因表达的一个重要
策略。据推测，miRNA调节着人类三分之一的基因。
| MicroRNA |
1. pre-miRNA
约70bp含microRNA茎环结构的pre-miRNA。
制备方式：化学合成、生物转录合成、pre-miRNA质粒表达载体、pre-miRNA病毒。
2. pri－miRNA
天然pri－miRNA
从染色体基因文库中调取300bp－1000bp完整的microRNA基因，克隆到质粒载体（普通载体或病毒载体），以强大的CMV启动子操纵该300bp－1000bp microRNA。
人工pri－miRNA
选择一个完整的microRNA基因，克隆到质粒载体（普通载体或病毒载体）。以人工合成的约70bp含miRNA茎环结构的目标pre-RNA替代原pre-RNA，并以pol Ⅱ/pol III 启动子操纵
、该microRNA结构单元。
MicroRNA的形式
miRNA基因是一类高度保守的基因家族，按其作用模式不同可分为三种：第一种以线虫lin-4为代表，作用时与靶标基因不完全互补结合，进而抑制翻译而不影响mRNA的稳定性（不改变mRNA丰度），这种miRNA是目前发现最多的种类；第二种以拟南芥miR-171为代表，作用时与靶标基因完全互补结合，作用方式和功能与siRNA非常类似，最后切割靶mRNA；第三种以let-7为代表，它具有以上两种作用模式：当与靶标基因完全互补结合时，直接靶向切割mRNA，如果蝇和Hela细胞中let-7直接介导RISC分裂切割靶mRNA；当与靶标基因不完全互补结合时，起调节基因表达的作用，如线虫中的let-7与靶mRNA3´端非翻译区不完全配对结合后，抑制调节基因的翻译。
研究表明MiRNAs在物种间具有高度的保守性、时序性和组织特异性——在特定的时间、组织才会表达。
细胞特异性或组织特异性是miRNA表达的主要特点，又如拟南芥中的miR-171仅在其花序中高水平表达，在某些组织低水平表达，在茎、叶等组织中却无任何表达的迹象；20-24h的果蝇胚胎提取物中可发现miR-12，却找不到miR3-miR6，在成年果蝇中表达的miR-1和let-7也无法在果蝇胚胎中表达，这同时体现了miRNA的又一特点——基因表达时序性。MiRNA表达的时序性和组织特异性暗示miRNA的分布可能决定组织和细胞的功能特异性，也可能参与了复杂的基因调控，对组织的发育起重要作用。
siRNA是RNAi途径的主要作用物,miRNA和siRNA很容易混淆，他们有许多共同点也有许多不同点。为了能够清楚地让读者弄清两者之间的差异之处，笔者特别将它们之间的差别划分入三个大的阶段：起源阶段、成熟阶段和功能阶段（即调节基因表达的作用阶段）。
在描述两者的差异之前，有必要先说一说它们的共同点：
1． MiRNA和siRNA都是由22个左右的核苷组成；
2． 它们都是Dicer酶的产物；
3． 它们在起干扰、调节作用时都会和RISC复合体结合；
4． 它们都可以在转录后和翻译水平干扰以抑制靶标基因的翻译；
两者之间的主要差异：
起源阶段
SiRNA：通常是外源的，如病毒感染和人工插入的dsRNA被剪切后产生外源基因进入细胞（注：病毒入侵，或者是自身合成RNA中出现错误，细胞内就会产生双链RNA，来阻止这些异常基因的表达）。
MiRNA：是内源性的，是一种非编码的RNA；由miRNA基因表达出最初的pri-miRNA分子。
成熟过程
SiRNA：直接来源是长链的dsRNA（通常为外源）；经过Dicer酶*切割形成双链siRNA,而且每个前体daRNA能够被切割成不定数量的siRNA片段。
MiRNA：在细胞核中转录的较大的pri-miRNA经由Drosha(一种RNAse Ⅲ酶)和Pasha（含有双链RNA结合区域）加工成为单链pre-miRNA；接着，发夹状、部分互补的pre-miRNA在细胞质中被Dicer*（一种RNAse Ⅲ酶）酶切割形成miRNA；在生物体中的表达具有时序性、保守性和组织特异性。
功能阶段
siRNA：它与RISC*（RNA诱导的沉默复合物，使用的AGO蛋白家族的成分为AGO2）结合，以RNAi途径行使功能，即通过与序列互补的靶标mRNA完全结合（与编码区结合），从而降解mRNA以达到抑制蛋白质翻译的目的；它通常用于沉默外源病毒、转座子活性。
MiRNA:它和RISC形成复合体(利用的AGO蛋白家族成员为AGO1)后与靶标mRNA通常发生不完全结合，并且结合的位点是mRNA的非编码区的3’端；它不会降解靶标mRNA，而只是阻止mRNA的翻译； miRNA能够调节与生长发育有关的基因。
注：RISC, RNA诱导的沉默复合物（RNA-induced silencing complex; RISC）的组装是在RNAi和miRNA通路中最为复杂的过程。新的研究表明，与siRNA和miRNA结合的RISC复合物并不完全相同其中的AGO蛋白质有AGO1和AGO2之分。刚产生的siRNAs和miRNAs都是双链结构，这种双链结构需要解螺旋才能被组装到RISC中发挥作用。组装后的复合物分别称为siRISC和miRISC。从dsRNA引发RNAi的发生大致划分为三个阶段，即启动、剪切和扩增。
Dicer酶：新的研究表明siRNA成熟需要Dicer-2和R2D2蛋白，而miRNA则依赖Dicer1和它的伴侣loqs蛋白。
MicroRNA
http://en.wikipedia.org/wiki/MicroRNA
A microRNA (abbreviated miRNA) is a short ribonucleic acid (RNA) molecule found in all eukaryotic cells, except those of fungi, algae, and marine plants.[citation needed] A microRNA molecule has very few nucleotides (an average of 22) compared with other RNAs.
MiRNAs are post-transcriptional regulators that bind to complementary sequences on target messenger RNA transcripts (mRNAs), usually resulting in translational repression or target degradation and gene silencing.[1][2] The human genome may encode over 1000 miRNAs,[3][4] which may target about 60% of mammalian genes[5][6] and are abundant in many human cell types.[7]
miRNAs show very different characteristics between plants and metazoans. In plants the miRNA complementarity to its mRNA target is nearly perfect, with no or few mismatched bases. In metazoans, on the other hand, miRNA complementarity typically encompasses the 5' bases 2-7 of the microRNA, the microRNA seed region,[5][8] and one miRNA can target many different sites on the same mRNA or on many different mRNAs. Another difference is the location of target sites on mRNAs. In metazoans, the miRNA target sites are in the three prime untranslated regions (3'UTR) of the mRNA. In plants, targets can be located in the 3' UTR but are more often in the coding region itself.[9] MiRNAs are well conserved in eukaryotic organisms and are thought to be a vital and evolutionarily ancient component of genetic regulation.[10][11][12][13]
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.[14][15][16][17][18][19][20] Different sets of expressed miRNAs are found in different cell types and tissues.[21]
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.[25] 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,[26][27] indicating the existence of a wider phenomenon.
NomenclatureUnder a standard nomenclature system, names are assigned to experimentally confirmed miRNAs before publication of their discovery.[28][29] 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 bar 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
Most microRNA genes are found in intergenic regions or in anti-sense orientation to genes[30] and contain their own miRNA gene promoter and regulatory units.[30][31][32][33] 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.[34] These are usually, though not exclusively, found in a sense orientation.[35][36] and thus usually are regulated together with their host genes.[34][37][38] 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,[31][39] 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.[31][40] The DNA template is not the final word on mature miRNA production: 6% of human miRNAs show RNA editing, 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.
TranscriptionmiRNA genes are usually transcribed by RNA polymerase II (Pol II).[31][40] 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),[31][35] and spliced. The product, called a primary miRNA (pri-miRNA), may be hundreds or thousands of nucleotides in length and contain one or more miRNA stem-loops.[31][35] When a stem-loop precursor is found in the 3’ UTR, a transcript may serve as a pri-miRNA and a mRNA.[35] 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.[41]
Nuclear processingA 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.[42] 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 resulting hairpin, known as a pre-miRNA (precursor-miRNA), has a two-nucleotide overhang at its 3’ end; it has 3' hydroxyl and 5' phosphate groups.
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.[43]
Perhaps as many as 16% of pri-miRNAs may be altered through nuclear RNA editing.[44][45][46] 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).[44]
Nuclear exportpre-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.[47]
Cytoplasmic processingIn the cytoplasm, the pre-miRNA hairpin is cleaved by the RNase III enzyme Dicer.[48] 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.[48] Overall hairpin length and loop size influence the efficiency of Dicer processing, and the imperfect nature of the miRNA:miRNA* pairing also affects cleavage.[48][49] 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 plantsmiRNA biogenesis in plants differs from metazoan 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.[50]
The RNA-induced silencing complexThe mature miRNA is part of an active RNA-induced silencing complex (RISC) containing Dicer and many associated proteins.[51] RISC is also known as a microRNA ribonucleoprotein complex (miRNP);[52] 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.[53][54][55] The position of the stem-loop may also influence strand choice.[56] 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.[57]
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.[58] 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).[58][59]
Additional RISC components include TRBP [human immunodeficiency virus (HIV) transactivating response RNA (TAR) binding protein],[60] PACT (protein activator of the interferon induced protein kinase (PACT), the SMN complex, fragile X mental retardation protein (FMRP), and Tudor staphylococcal nuclease-domain-containing protein (Tudor-SN).[61][62]
Mode of SilencingGene silencing may occur either via mRNA degradation or preventing mRNA from being translated. 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.[63]
miRNA turnoverTurnover 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.[64]
Decay of mature miRNAs in animals is mediated by the 5´-to-3´ exoribonuclease XRN2, also known as Rat1p.[65] 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.[64]
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.[64]
Cellular functionsThe 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.[66] Perfect or near perfect base pairing with the target RNA promotes cleavage of the RNA.[67] This is the primary mode of plant microRNAs.[68] In animals, microRNAs more often only partially base pair and inhibit protein translation of the target mRNA[69] (this exists in plants as well but is less common).[68] MicroRNAs that are partially complementary to a target can also speed up deadenylation, causing mRNAs to be degraded sooner.[70] For partially complementary microRNAs to recognise their targets, nucleotides 2–7 of the miRNA (its 'seed region'[5][8]) still have to be perfectly complementary.[71] miRNAs occasionally also cause histone modification and DNA methylation of promoter sites, which affects the expression of target genes.[72][73]
Unlike plant microRNAs, the animal microRNAs target a diverse set of genes.[8] 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.[74]
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),[75] but has also been demonstrated for endogenous microRNA.[76]
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 ("junk") DNA.[77]
EvolutionMicroRNAs are significant phylogenetic markers because of their astonishingly low rate of evolution.[78] 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[79] and perhaps, ultimately, complex life.[80] Indeed, rapid bursts of morphological innovation are generally associated with a high rate of microRNA accumulation.[78][79]
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.[81] 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),[80] suggesting that once a microRNA gains a function it undergoes extreme purifying selection.[81] At this point, a microRNA is rarely lost from an animal's genome,[80] although microRNAs which are more recently derived (and thus presumably non-functional) are frequently lost.[81] 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.[82]
MicroRNAs feature in the genomes of most eukaryotic organisms, from the brown algae[83] to the metazoa. Across all species, in excess of 5000 had been identified by March 2010.[84] Whilst short RNA sequences (50 – hundreds of base pairs) of a broadly comparable function occur in bacteria, bacteria lack true microRNAs.[85]
Experimental detection and manipulation of miRNAMicroRNA 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.[86] 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.[87] MicroRNAs can be both discovered and profiled by high-throughput sequencing methods.[88] The activity of an miRNA can be experimentally inhibited using a locked nucleic acid (LNA) oligo, a Morpholino oligo[89][90] or a 2'-O-methyl RNA oligo.[91] Additionally, a specific miRNA can be silenced by a complementary antagomir. MicroRNA maturation can be inhibited at several points by steric-blocking oligos.[92] The miRNA target site of an mRNA transcript can also be blocked by a steric-blocking oligo.[93][94] For the “in situ” detection of miRNA, the use of LNA is currently the only efficient method.[95] The locked conformation of LNA results in enhanced hybridization properties and increases sensitivity and selectivity, making it ideal for detection of short miRNA.[96]
miRNA and diseaseJust 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.[97]
miRNA and cancerSeveral miRNAs have been found to have links with some types of cancer.[98][99] MicroRNA-21 is one of the first microRNAs that was 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.[98] 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.[100]
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.[101]
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.[102]
Transgenic mice that over-express or lack specific miRNAs have provided insight into the role of small RNAs in various malignancies.[103]
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.[104][105]
miRNA and heart diseaseThe 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.[106][107] miRNA expression profiling studies demonstrate that expression levels of specific miRNAs change in diseased human hearts, pointing to their involvement in cardiomyopathies.[108][109][110] 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.[107][111][112][113][114][115]
miRNA and the nervous systemmiRNAs appear to regulate the nervous system.[116] 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).[117] Some studies find altered miRNA expression in schizophrenia.[118][119]
miRNA and non-coding RNAsWhen 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).[120] Since then, the advent of bioinformatics approaches combined with genome tiling studies examining the transcriptome,[121] systematic sequencing of full length cDNA libraries,[122] and experimental validation[123] (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.[124]
See also
References
External links
Look up microRNA or miRNA in Wiktionary, the free dictionary.
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