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Új oldal, tartalma: „{{építés alatt}} bélyegkép|400px|Pre-miRNS a Pri-miRNS helyett a mechanizmus első pontjában. A mikro-RNS hatása [[mRNS-re]] bélyegkép|400px|miRNS-hurkok, az érett miRNS-ek pirossal A '''mikro-RNS''' ('''miRNS''') kis, egyszálú nem kódoló RNS 21–23 nukleotiddal.<ref name="Metazoan MicroRNAs">{{cite journal|author=Bartel DP|title=Metazoan MicroRNAs|journal=Cell|volume=173|issue=1|…”
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Pre-miRNS a Pri-miRNS helyett a mechanizmus első pontjában. A mikro-RNS hatása mRNS-re
miRNS-hurkok, az érett miRNS-ek pirossal

A mikro-RNS (miRNS) kis, egyszálú nem kódoló RNS 21–23 nukleotiddal.[1] Növényekben, állatokban és egyes vírusokban találhatók, és az RNS-csendesítésben és a poszttranszlációs génexpresszió-szabályzásban fontosak.[2][3] A miRNS-ek a megfelelő mRNS-ek kopmlementer szakaszaihoz kötnek,[4] majd ezeket az alábbi folyamatok egyikével csendesítik:[1][5]

  1. Felbontás két részre,
  2. Destabilizáció a poli(A)-farok rövidítése vagy
  3. fehérjékké való transzláció csökkentése.

Állati sejtekben a miRNS-ek elsősorban az mRNS destabilizációjával hatnak.[5][6]

A miRNS-ek a kis interferáló RNS-ekhez (siRNS) hasonlítanak az RNS-interferencia (RNSi) útjában, azonban a miRNS-ek önmagukra visszahajló rövid hajtűket alkotó RNS-transzkriptum-részekből származnak, míg a siRNS-ek hosszabb kétszálú RNS-részekből.[2] A humán genom több mint 1900 miRNS-t kódolhat,[7][8] Azonban csak mintegy 500 humán miRNS jelent bona fide miRNS-t a kézzel kezelt MirGeneDB miRNS-gén-adatbázisban.[9]

Számos emlőssejttípusban sok miRNS található:[10][11] ezek a humán és más emlősgének mintegy 60%-át célozzák.[12][13] Sok miRNS evolúciósan állandósult, vagyis fontos biológiai funkcióik lehetnek.[14][1] Például 90 miRNS-család legalább az emlősök és a halak közös őséig visszamenőleg állandósult, és ezeknek fontos funkcióik vannak, melyeket ezek egy vagy több tagjának eltávolításával végzett egérkísérletek mutattak ki.[1]

Történet

Az első miRNS-t 1993-ban fedezték fel.[15] Azonban csak 2000-ben ismerték el önálló biológiaiszabályzó-osztályként.[16][17][18][19][20] a miRNS-kutatás számos eltérő miRNS-csoportot mutatott ki eltérő sejttípusokban és szövetekben,[11][21] valamint számos szerepet a miRNS-eknek a növényi és állati fejlődésben és sok más biológiai folyamatban.[22][23][24][25][26][27][28] A nem megfelelő miRNS-expresszió számos betegségben megjelenik. Vizsgálnak miRNS-alapú terápiákat.[29][30][31][32]

Az első miRNS-t 1993-ban fedezte fel Victor Ambros, Lee és Feinbaum. Azonban további vizsgálatához Gary Ruvkun, Wightman és Ha munkája kellett.[15][33] E csoportok egymás után közöltek tanulmányokat a lin-4 génről, mely a Caenorhabditis elegans-lárva fejlődését irányítja a lin-14 gén repressziójával. Miután Lee et al. izolálták a lin-4 miRNS-t, észrevették, hogy nem fehérjekódoló mRNS-t kódol, hanem rövid nem kódoló RNS-t, melyek egyike a lin-14-mRNS 3'-transzlálatlanrégiójának több szakaszával részben komplementer.[15] Feltételezésük szerint a lin-4 a lin-14 mRNS LIN-14 fehérjévé való transzlációját gátolta, és úgy gondolták, hogy a lin-4 csak gyűrűsférgekre jellemző.

2000-ben fedezték fel a második kis RNS-t, a let-7-RNS-t, mely a lin-41-et represszálja a C. elegans későbbi fejlődési átmenetéhez.[16] Ezt sok fajban állandósultnak találták, ahhoz a feltételezéshez vezetve, hogy a let-7-RNS és más „kis temporális RNS-ek” számos állat – beleértve az embert – fejlődésének időzítését szabályozhatják.[17]

2001-ben a lin-4 és let-7 RNS-ekről kiderítették, hogy egy, a C. elegans, a Drosophila és az ember sejtjeiben jelenlévő nagy kis-RNS-osztály tagja.[18][19][20] Ennek sok RNS-e hasonlított a lin-4 és let-7-RNS-ekre, eltekintve a fejlődésidőzítés szabályzásának nem megfelelő expressziós mintával. Ez alapján feltételezték, hogy a legtöbb más szabályzó utakban vesz részt. Ekkor kezdték el a kis szabályzó RNS-eket mikro-RNS-nek nevezni.[18][19][20]

Az első miRNS-deregulációval összefüggő humán betegség a B-sejtes krónikus limfocitás leukémia volt. E betegségben a miRNS-ek egyszerre működnek tumorszupresszorként és onkogénként.[34]

Nevezéktan

A szabványos nevezéktanban a kísérletileg igazolt miRNS-ek nevüket közlés előtt kapják.[35][36] A „miR” prefixumot kötőjel, majd szám követi, ez utóbbi gyakran a megnevezés sorrenjét jelenti. Például a miR-124 korábban kapta nevét, és korábban fedezték fel a miR-456-nál. A nagybetűs „miR-” érett miRNS-t jelent, a nagybetű nélküli „mir-” a pre- és pri-miRNS-re.[37] A miRNS-kódoló gének ugyane 3 betűs prefixumot kapják génnevezéktanuknak megfelelően – példák miRNS-gén-nevekre a mir-1 C. elegans és Drosophila esetén, Mir1 Rattus norvegicus esetén és MIR25 emberben.

Az egy-két nukleotid kivételével teljesen eltérő szekvenciák további kisbetűt kapnak. Például a miR-124a a miR-124b közeli rokona. Például:

hsa-miR-181a: 5’-aacauucaACgcugucggugAgu-3’
hsa-miR-181b: 5’-aacauucaUUgcugucggugGgu-3’

A pre-, pri-miRNS-ek és az azonos érett miRNS-hez vezető különböző helyű gének további kötőjelet és számot kapnak. Például a hsa-mir-194-1 és hsa-mir-194-2 azonos érett miRNS-t (hsa-miR-194) hoz létre, de eltérő genombeli helyről származnak.

A faj hárombetűs prefixummal van jelölve – például a hsa-miR-124 humán, az oar-miR-123 bárány-miRNS. További prefixumok például a vírusokat jelölő v vagy a Drosophilát jelölő d.

Ha két érett miRNS azonos pre-miRNS ellentétes karjairól származik és nagyjából ugyanannyi van belőlük, -3p vagy -5p utótagot kapnak (korábban s (szenz) vagy as (antiszenz) utótaggal is jelölték). Azonban a hajtű egyik karjáról származó miRNS általában sokkal nagyobb mennyiségben van jelen, mint a másikról származó,[2] ez esetben a nevet követő csillag a kisebb mennyiségben a másik karról keletkező miRNS-t jelenti. Például a miR-124 és a miR-124* azonos pre-miRNS hajtűvel rendelkeznek, de sokkal több a miR-124.

Célok

A növényi miRNS-ek közel tökéletesen párosodnak mRNS céljaikkal, a génrepressziót a célpont lebontásával elérve.[22][38] Ezzel szemben az állati miRNS-ek cél-mRNS-üket csupán 6–8 nukleotiddal (magrégió) ismerik fel a kezdetükön,[12][39][40] ami kevés a cél-mRNS-bontás elindításához.[4] A kombinációszabályzás fontos az állatok miRNS-szabályzásában.[4][41] Egy adott miRNS több száz mRNS-célponttal rendelkezhet, és egy célpontot több miRNS szabályozhatja.[13][42]

Adott miRNS által célzott egyedi mRNS-ek átlagos száma becsléstől függően eltér,[43] de több megközelítés szerint az emlős-miRNS-ek számos egyedi célponttal rendelkezhetnek. Például a gerincesekben állandósult miRNS-eknek átlagosan mintegy 400 állandó célpontjuk van.[13] Ugyanígy kísérletek szerint egy miRNS több száz egyedi mRNS stabilitását csökkentheti.[44] Más kísérletek szerint egy miRNS több száz fehérje termelését represszálhatja, de gyakran ez enyhe – kevesebb mint 2-szeres.[45][46]

Szintézis

A miRNS-gének akár 40%-a más gének intronjaiban vagy akár exonjaiban lehet.[47] Ezek gyakran szenz elrendezésben vannak,[48][49] így szabályzásuk a gazdagénekével együtt történik.[47][50][51]

A DNS-templáttal nem ér véget a miRNS-érés: a humán miRNS-ek 6%-a helyspecifikus RNS-szerkesztést mutat (izomiR) a DNS által kódolttól eltérő termékek létrehozásához. Ez a genom által kódolthoz képest növeli a miRNS-hatás diverzitását.

Transzkripció

A miRNS-géneket általában az RNS-polimeráz II (Pol II) írja át.[52][53] Gyakran köt a szekvenciához közeli promotert, mely a pre-miRNS hajtűhurka. Az így létrejött átirat 5'-végén speciálisan módosult nukleotid jön létre, poli(A)-farkat kap,[52][48] és leválik. Az állati miRNS-ek kezdetben egy mintegy 80 nukleotidos RNS-törzskörben keletkeznek, mely egy néhány száz nukleotidos miRNS-prekurzor, a pri-miRNS része.[52][48] Ha egy törzskörprekurzor van a 3'-UTR-ben, az átirat pri-miRNS és mRNS is lehet.[48] Az RNS-polimeráz III (Pol III) néhány miRNS-t átír, különösen a korai Alu-szekvenciákkal rendelkező, a transzfer- és az emlős-szélesszórtismétlődés (MWIR) promotereket.[54]

Magi feldolgozás

Humán Drosha fehérje röntgenkrisztallográfia-képe két DGCR8-cal (zöld) alkotott komplexben. A Drosha két ribonukleáz III-domént (kék, narancs), egy kétszálú-RNS-kötő domént (sárga) és egy összekötő domént (szürke) tartalmaz két cinkkel. PDB: 5B16

Egy pri-miRNS 1–6 miRNS-prekurzort tartalmazhat. Ezek mintegy 70 nukleotidból állnak, és a hatékony feldolgozáshoz szükséges szekvenciák veszik körül.

A kétszálú RNS-szerkezetet (dsRNS) a pri-miRNS-ek hajtűiben a DiGeorge-szindróma, 8. fontos régió (DGCR8, gerinctelenekben Pasha) veszi körül, mely nevét a DiGeorge-szindrómával való kapcsolatáról kapta. Ez az RNS-vágó Drosha enzimmel asszociál mikroprocesszor-komplexet alkotva.[55][56] E komplexben a DGCR8 a katalitikus RNáz III-domént hajtűk pri-miRNS-ekről való leválasztására használja mintegy 11 nukleotiddal a hajtűalap előtt (egy helikális dsRNS-fordulattal a törzsön belül).[57][58] A termék kétnukleotidos többlettel rendelkezik a 3'-végen, 3'-hidroxil- és 5'-foszfátcsoportjai vannak. Gyakran ezt pre-miRNS-nek nevezik. Ismertek a pre-miRNS utáni fontos szekvenciamotívumok.[59][60][61]

Az intronokból közvetlenül a mikroprocesszor-komplex megkerülésével leválasztott pre-miRNS-ek a mirtronok.[62] Ismertek mirtronok a Drosophilában, a C. elegansban és emlősökben.[63][64]

A pre-miRNS-ek 16%-át módosíthatja a magi RNS-szerkesztés.[65][66][67] A leggyakoribb az RNS-re ható adenozin-deaminázok (ADAR) általi módosítás, melyek az adenozint inozinná (A→I) alakítják. Az RNS-szerkesztés leállíthatja a magi folyamatot (például a pri-miR-142-ben a Tudor-SN ribonukleáz általi bomláshoz vezet) és a későbbi folyamatokat, például a citoplazmatikus miRNS-feldolgozást és a célspecificitást (például a miR-376 magrégiójának változtatásával a központi idegrendszerben).[65]

Magi kivitel

A humán exportin-5 (piros), a Ran-GTP (sárga) és egy pre-miRNS (zöld) komplexe. Látható a kétnukleotidos többletet felismerő elem (narancs). Forrás: PDB: 3A6P

A pre-miRNS-hajtűk a magból a nukleocitoplazmatikus szállító exportin-5-öt tartalmazó folyamatban távoznak. E fehérje a karioferinek családjának tagja, és felismeri a Drosha által megmaradt kétnukleotidos többletet a per-miRNS-hajtű 3'-végén. Az exportin-5-mediált transzport energiafüggő, a Ran fehérjéhez kötött guanozin-trifoszfátot használ.[68]

Citoplazmatikus feldolgozás

A citoplazmában a pre-miRNS hajtűt a Dicer RNáz III bontja.[69] Ez az endoribonukleáz a hajtű 5'- és 3'-végeivel kölcsönhat,[70] és elvágja a 3'- és 5'-karokat összekötő kapcsolatokat, mintegy 22 nukleotid hosszú nem tökéletes miRNS:miRNS* duplexet adva.[69] A teljes hajtűhossz és a körméret befolyásolják a Dicer hatékonyságát. Hogy a miRNS:miRNS* pár nem tökéletes, befolyásolja az elválást is.[69][71] Egyes G-gazdag pre-miRNS-ek G-kvadruplex szerkezetet is alkothatnak a törzskörszerkezet miatt – például a humán pre-miRNS 92b a Dicer-mediált bontásnak ellenálló G-kvadruplexet alkot a citoplazmában.[72] Bár a duplex bármely szála funkcionális miRNS-ként működhet, csak egy szál kerül az RNS-indukált csendesítőkomplexbe, ahol a miRNS és mRNS célja kölcsönhatnak.

Míg a legtöbb miRNS a sejtben van, a keringő vagy extracelluláris miRNS-ek sejten kívül is megtalálhatók, beleértve számos biológiai folyadékot és sejtkultúraközeget.[73][74]

Szintézise növényekben

A miRNS-szintézis növényekben főleg a magi feldolgozásban és kivitelben tér el az állatokétól. Nem két eltérő enzim bontja a miRNS-eket egyszer a magban és egyszer azon kívül, hanem mindkét bontást a Dicer-like1 (DL1) enzim végzi. Ez csak a növényi sejtek magjában expresszálódik, így feltehetően mindkét reakció a magban történik. A növényi miRNS:miRNS* duplexek magból való kivitele előtt a 3'-végeket az RNS-metiltranszferáz Hua-erősítő 1 (HEN1) metilálja. Ezt az exportin-5-homológ Hasty (HST) szállítja a magból a citoplazmába, ahol kettéválnak, az érett miRNS a RISC-be kerül.[75]

RNS-indukált csendesítőkomplex

Bővebben: RNS-indukált csendesítőkomplex

Az érett miRNS aktív RNS-indukált csendesítőkomplex (RISC) része, ahol a Dicer és sok kapcsolódó fehérje van.[76] A RISC-et nevezik mikro-RNS-ribonukleoprotein-komplexnek (miRNP) is.[77] A miRNS-sel rendelkező RISC-et nevezik miRISC-nek is.

A pre-miRNS Dicer általi feldolgozása feltehetően a duplex kibontásával együtt történik. Általában egy szál van a miRISC-ben, melyet termodinamikai instabilitás és a másik szálnál gyengébb 5'-végi bázispárosodás alapján választ ki.[78][79][80] A törzskör helye is befolyásolhatja a szálválasztást.[81] 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.[82]

AGO2 (grey) in complex with a microRNA (light blue) and its target mRNA (dark blue)

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.[83] 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 germline and hematopoietic stem cells).[77][83]

Additional RISC components include TRBP [human immunodeficiency virus (HIV) transactivating response RNA (TAR) binding protein],[84] PACT (protein activator of the interferon-induced protein kinase), 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.[68][85][86]

Mode of silencing and regulatory loops

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.[87] It has been demonstrated that given complete complementarity between the miRNA and target mRNA sequence, Ago2 can cleave the mRNA and lead to direct mRNA degradation. In the absence of complementarity, silencing is achieved by preventing translation.[44] The relation of miRNA and its target mRNA can be based on the simple negative regulation of a target mRNA, but it seems that a common scenario is the use of a "coherent feed-forward loop", "mutual negative feedback loop" (also termed double negative loop) and "positive feedback/feed-forward loop". Some miRNAs work as buffers of random gene expression changes arising due to stochastic events in transcription, translation and protein stability. Such regulation is typically achieved by the virtue of negative feedback loops or incoherent feed-forward loop uncoupling protein output from mRNA transcription.

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.[88]

Decay of mature miRNAs in Caenorhabditis elegans is mediated by the 5'-to-3' exoribonuclease XRN2, also known as Rat1p.[89] 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 been described.[88]

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 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.[88]

Cellular functions

Interaction of microRNA with protein translation process. Several translation repression mechanisms 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.[90] 40S and 60S are light and heavy components of the ribosome, 80S is the assembled ribosome bound to mRNA, eIF4F is a 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 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 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.[91] Perfect or near perfect base pairing with the target RNA promotes cleavage of the RNA.[92] This is the primary mode of plant miRNAs.[93] In animals the match-ups are imperfect.

For partially complementary microRNAs to recognise their targets, nucleotides 2–7 of the miRNA (its 'seed region'[12][39]) must be perfectly complementary.[94] Animal miRNAs inhibit protein translation of the target mRNA[95] (this is present but less common in plants).[93] Partially complementary microRNAs can also speed up deadenylation, causing mRNAs to be degraded sooner.[96] 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 in zebrafish, as well as on bantam-miRNA and miR-9 in Drosophila cultured cells, shows that translational repression is caused by the disruption of translation initiation, independent of mRNA deadenylation.[97][98]

miRNAs occasionally also cause histone modification and DNA methylation of promoter sites, which affects the expression of target genes.[99][100]

Nine mechanisms of miRNA action are described and assembled in a unified mathematical model:[90]

  • Cap-40S initiation inhibition;
  • 60S Ribosomal unit joining inhibition;
  • Elongation inhibition;
  • Ribosome drop-off (premature termination);
  • Co-translational nascent protein degradation;
  • Sequestration in P-bodies;
  • mRNA decay (destabilisation);
  • mRNA cleavage;
  • Transcriptional inhibition through microRNA-mediated chromatin reorganization followed by gene silencing.

It is often impossible to discern these mechanisms using experimental data about stationary reaction rates. Nevertheless, they are differentiated in dynamics and have different kinetic signatures.[90]

Unlike plant microRNAs, the animal microRNAs target diverse genes.[39] 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.[101] There is a strong correlation between ITPR gene regulations and mir-92 and mir-19.[102]

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),[103] but has also been demonstrated for endogenous microRNA.[104]

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 (genes having a similar structure indicating divergence from a common ancestral gene). 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.[105]

miRNAs are also found as extracellular circulating miRNAs.[106] Circulating miRNAs are released into body fluids including blood and cerebrospinal fluid and have the potential to be available as biomarkers in a number of diseases.[106][107]Some researches show that mRNA cargo of exosomes may have a role in implantation, they can savage an adhesion between trophoblast and endometrium or support the adhesion by down regulating or up regulating expression of genes involved in adhesion/invasion.[108]

Moreover, miRNA as miR-183/96/182 seems to play a key role in circadian rhythm.[109]

Evolution

miRNAs are well conserved in both plants and animals, and are thought to be a vital and evolutionarily ancient component of gene regulation.[110][111][112][113][114] While core components of the microRNA pathway are conserved between plants and animals, miRNA repertoires in the two kingdoms appear to have emerged independently with different primary modes of action.[115][116]

microRNAs are useful phylogenetic markers because of their apparently low rate of evolution.[117] microRNAs' origin as a regulatory mechanism developed from previous RNAi machinery that was initially used as a defense against exogenous genetic material such as viruses.[118] 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[119] and perhaps, ultimately, complex life.[114] Rapid bursts of morphological innovation are generally associated with a high rate of microRNA accumulation.[117][119]

New microRNAs are created in multiple ways. Novel microRNAs can originate from 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.[120] microRNAs can also form from inverted duplications of protein-coding sequences, which allows for the creation of a foldback hairpin structure.[121] 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),[114] suggesting that once a microRNA gains a function, it undergoes purifying selection.[120] Individual regions within an miRNA gene face different evolutionary pressures, where regions that are vital for processing and function have higher levels of conservation.[122] At this point, a microRNA is rarely lost from an animal's genome,[114] although newer microRNAs (thus presumably non-functional) are frequently lost.[120] In Arabidopsis thaliana, the net flux of miRNA genes has been predicted to be between 1.2 and 3.3 genes per million years.[123] This makes them a valuable phylogenetic marker, and they are being looked upon as a possible solution to outstanding phylogenetic problems such as the relationships of arthropods.[124] On the other hand, in multiple cases microRNAs correlate poorly with phylogeny, and it is possible that their phylogenetic concordance largely reflects a limited sampling of microRNAs.[125]

microRNAs feature in the genomes of most eukaryotic organisms, from the brown algae[126] to the animals. However, the difference in how these microRNAs function and the way they are processed suggests that microRNAs arose independently in plants and animals.[127]

Focusing on the animals, the genome of Mnemiopsis leidyi[128] appears to lack recognizable microRNAs, as well as the nuclear proteins Drosha and Pasha, which are critical to canonical microRNA biogenesis. It is the only animal thus far reported to be missing Drosha. MicroRNAs play a vital role in the regulation of gene expression in all non-ctenophore animals investigated thus far except for Trichoplax adhaerens, the only known member of the phylum Placozoa.[129]

Across all species, in excess of 5000 different miRNAs had been identified by March 2010.[130] Whilst short RNA sequences (50 – hundreds of base pairs) of a broadly comparable function occur in bacteria, bacteria lack true microRNAs.[131]

Experimental detection and manipulation

While researchers focused on miRNA expression in physiological and pathological processes, various technical variables related to microRNA isolation emerged. The stability of stored miRNA samples has been questioned.[74] microRNAs degrade much more easily than mRNAs, partly due to their length, but also because of ubiquitously present RNases. This makes it necessary to cool samples on ice and use RNase-free equipment.[132]

microRNA expression can be quantified in a two-step polymerase chain reaction process of modified RT-PCR followed by quantitative PCR. Variations of this method achieve absolute or relative quantification.[133] 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.[134] microRNAs can be both discovered and profiled by high-throughput sequencing methods (microRNA sequencing).[135] The activity of an miRNA can be experimentally inhibited using a locked nucleic acid (LNA) oligo, a Morpholino oligo[136][137] or a 2'-O-methyl RNA oligo.[138] A specific miRNA can be silenced by a complementary antagomir. microRNA maturation can be inhibited at several points by steric-blocking oligos.[139][140] The miRNA target site of an mRNA transcript can also be blocked by a steric-blocking oligo.[141] For the "in situ" detection of miRNA, LNA[142] or Morpholino[143] 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.[144]

High-throughput quantification of miRNAs is error prone, for the larger variance (compared to mRNAs) that comes with methodological problems. mRNA-expression is therefore often analyzed to check for miRNA-effects in their levels (e.g. in[145]). Databases can be used to pair mRNA- and miRNA-data that predict miRNA-targets based on their base sequence.[146][147] 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.[148][149]

Human and animal diseases

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.[150]

Inherited diseases

A mutation in the seed region of miR-96 causes hereditary progressive hearing loss.[151]

A mutation in the seed region of miR-184 causes hereditary keratoconus with anterior polar cataract.[152]

Deletion of the miR-17~92 cluster causes skeletal and growth defects.[153]

Cancer

Role of miRNA in a cancer cell

The first human disease known to be associated with miRNA deregulation was chronic lymphocytic leukemia.[154] Many other miRNAs also have links with cancer and accordingly are sometimes referred to as "oncomirs".[155] In malignant B cells miRNAs participate in pathways fundamental to B cell development like B-cell receptor (BCR) signalling, B-cell migration/adhesion, cell-cell interactions in immune niches and the production and class-switching of immunoglobulins. MiRNAs influence B cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and memory B cells.[156]

Another role for miRNA in cancers is to use their expression level for prognosis. In NSCLC samples, low miR-324a levels may serve as an indicator of poor survival.[157] Either high miR-185 or low miR-133b levels may correlate with metastasis and poor survival in colorectal cancer.[158]

Furthermore, specific miRNAs may be associated with certain histological subtypes of colorectal cancer. For instance, expression levels of miR-205 and miR-373 have been shown to be increased in mucinous colorectal cancers and mucin-producing Ulcerative Colitis-associated colon cancers, but not in sporadic colonic adenocarcinoma that lack mucinous components.[159] In-vitro studies suggested that miR-205 and miR-373 may functionally induce different features of mucinous-associated neoplastic progression in intestinal epithelial cells.[159]

Hepatocellular carcinoma cell proliferation may arise from miR-21 interaction with MAP2K3, a tumor repressor gene.[160] Optimal treatment for cancer involves accurately identifying patients for risk-stratified therapy. Those with a rapid response to initial treatment may benefit from truncated treatment regimens, showing the value of accurate disease response measures. Cell-free circulating miRNAs (cimiRNAs) are highly stable in blood, are overexpressed in cancer and are quantifiable within the diagnostic laboratory. In classical Hodgkin lymphoma, plasma miR-21, miR-494, and miR-1973 are promising disease response biomarkers.[161] Circulating miRNAs have the potential to assist clinical decision making and aid interpretation of positron emission tomography combined with computerized tomography. They can be performed at each consultation to assess disease response and detect relapse.

MicroRNAs have the potential to be used as tools or targets for treatment of different cancers.[162] The specific microRNA, miR-506 has been found to work as a tumor antagonist in several studies. A significant number of cervical cancer samples were found to have downregulated expression of miR-506. Additionally, miR-506 works to promote apoptosis of cervical cancer cells, through its direct target hedgehog pathway transcription factor, Gli3.[163][164]

DNA repair and cancer

Many miRNAs can directly target and inhibit cell cycle genes to control cell proliferation. A new strategy for tumor treatment is to inhibit tumor cell proliferation by repairing the defective miRNA pathway in tumors.[165] Cancer is caused by the accumulation of mutations from either DNA damage or uncorrected errors in DNA replication.[166] Defects in DNA repair cause the accumulation of mutations, which can lead to cancer.[167] Several genes involved in DNA repair are regulated by microRNAs.[168]

Germline mutations in DNA repair genes cause only 2–5% of colon cancer cases.[169] However, altered expression of microRNAs, causing DNA repair deficiencies, are frequently associated with cancers and may be an important causal factor. Among 68 sporadic colon cancers with reduced expression of the DNA mismatch repair protein MLH1, most were found to be deficient due to epigenetic methylation of the CpG island of the MLH1 gene.[170] However, up to 15% of MLH1-deficiencies in sporadic colon cancers appeared to be due to over-expression of the microRNA miR-155, which represses MLH1 expression.[171]

In 29–66%[172][173] of glioblastomas, DNA repair is deficient due to epigenetic methylation of the MGMT gene, which reduces protein expression of MGMT. However, for 28% of glioblastomas, the MGMT protein is deficient, but the MGMT promoter is not methylated.[172] In glioblastomas without methylated MGMT promoters, the level of microRNA miR-181d is inversely correlated with protein expression of MGMT and the direct target of miR-181d is the MGMT mRNA 3'UTR (the three prime untranslated region of MGMT mRNA).[172] Thus, in 28% of glioblastomas, increased expression of miR-181d and reduced expression of DNA repair enzyme MGMT may be a causal factor.

HMGA proteins (HMGA1a, HMGA1b and HMGA2) are implicated in cancer, and expression of these proteins is regulated by microRNAs. HMGA expression is almost undetectable in differentiated adult tissues, but is elevated in many cancers. HMGA proteins are polypeptides of ~100 amino acid residues characterized by a modular sequence organization. These proteins have three highly positively charged regions, termed AT hooks, that bind the minor groove of AT-rich DNA stretches in specific regions of DNA. Human neoplasias, including thyroid, prostatic, cervical, colorectal, pancreatic and ovarian carcinomas, show a strong increase of HMGA1a and HMGA1b proteins.[174] Transgenic mice with HMGA1 targeted to lymphoid cells develop aggressive lymphoma, showing that high HMGA1 expression is associated with cancers and that HMGA1 can act as an oncogene.[175] HMGA2 protein specifically targets the promoter of ERCC1, thus reducing expression of this DNA repair gene.[176] ERCC1 protein expression was deficient in 100% of 47 evaluated colon cancers (though the extent to which HGMA2 was involved is not known).[177]

Single Nucleotide polymorphisms (SNPs) can alter the binding of miRNAs on 3'UTRs for example the case of hsa-mir181a and hsa-mir181b on the CDON tumor suppressor gene.[178]

Heart disease

The global role of miRNA function in the heart has been addressed by conditionally inhibiting miRNA maturation in the murine heart. This revealed that miRNAs play an essential role during its development.[179][180] miRNA expression profiling studies demonstrate that expression levels of specific miRNAs change in diseased human hearts, pointing to their involvement in cardiomyopathies.[181][182][183] Furthermore, animal studies on specific miRNAs 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.[180][184][185][186][187][188] Another role for miRNA in cardiovascular diseases is to use their expression levels for diagnosis, prognosis or risk stratification.[189] miRNA's in animal models have also been linked to cholesterol metabolism and regulation.

miR-712

Murine microRNA-712 is a potential biomarker (i.e. predictor) for atherosclerosis, a cardiovascular disease of the arterial wall associated with lipid retention and inflammation.[190] Non-laminar blood flow also correlates with development of atherosclerosis as mechanosenors of endothelial cells respond to the shear force of disturbed flow (d-flow).[191] A number of pro-atherogenic genes including matrix metalloproteinases (MMPs) are upregulated by d-flow,[191] mediating pro-inflammatory and pro-angiogenic signals. These findings were observed in ligated carotid arteries of mice to mimic the effects of d-flow. Within 24 hours, pre-existing immature miR-712 formed mature miR-712 suggesting that miR-712 is flow-sensitive.[191] Coinciding with these results, miR-712 is also upregulated in endothelial cells exposed to naturally occurring d-flow in the greater curvature of the aortic arch.[191]

Origin

Pre-mRNA sequence of miR-712 is generated from the murine ribosomal RN45s gene at the internal transcribed spacer region 2 (ITS2).[191] XRN1 is an exonuclease that degrades the ITS2 region during processing of RN45s.[191] Reduction of XRN1 under d-flow conditions therefore leads to the accumulation of miR-712.[191]

Mechanism

MiR-712 targets tissue inhibitor of metalloproteinases 3 (TIMP3).[191] TIMPs normally regulate activity of matrix metalloproteinases (MMPs) which degrade the extracellular matrix (ECM). Arterial ECM is mainly composed of collagen and elastin fibers, providing the structural support and recoil properties of arteries.[192] These fibers play a critical role in regulation of vascular inflammation and permeability, which are important in the development of atherosclerosis.[193] Expressed by endothelial cells, TIMP3 is the only ECM-bound TIMP.[192] A decrease in TIMP3 expression results in an increase of ECM degradation in the presence of d-flow. Consistent with these findings, inhibition of pre-miR712 increases expression of TIMP3 in cells, even when exposed to turbulent flow.[191]

TIMP3 also decreases the expression of TNFα (a pro-inflammatory regulator) during turbulent flow.[191]  Activity of TNFα in turbulent flow was measured by the expression of TNFα-converting enzyme (TACE) in blood. TNFα decreased if miR-712 was inhibited or TIMP3 overexpressed,[191] suggesting that miR-712 and TIMP3 regulate TACE activity in turbulent flow conditions.

Anti-miR-712 effectively suppresses d-flow-induced miR-712 expression and increases TIMP3 expression.[191] Anti-miR-712 also inhibits vascular hyperpermeability, thereby significantly reducing atherosclerosis lesion development and immune cell infiltration.[191]

Human homolog microRNA-205

The human homolog of miR-712 was found on the RN45s homolog gene, which maintains similar miRNAs to mice.[191] MiR-205 of humans share similar sequences with miR-712 of mice and is conserved across most vertebrates.[191] MiR-205 and miR-712 also share more than 50% of the cell signaling targets, including TIMP3.[191]

When tested, d-flow decreased the expression of XRN1 in humans as it did in mice endothelial cells, indicating a potentially common role of XRN1 in humans.[191]

Kidney disease

Targeted deletion of Dicer in the FoxD1-derived renal progenitor cells in a murine model resulted in a complex renal phenotype including expansion of nephron progenitors, fewer renin cells, smooth muscle arterioles, progressive mesangial loss and glomerular aneurysms.[194] High throughput whole transcriptome profiling of the FoxD1-Dicer knockout mouse model revealed ectopic upregulation of pro-apoptotic gene, Bcl2L11 (Bim) and dysregulation of the p53 pathway with increase in p53 effector genes including Bax, Trp53inp1, Jun, Cdkn1a, Mmp2, and Arid3a. p53 protein levels remained unchanged, suggesting that FoxD1 stromal miRNAs directly repress p53-effector genes. Using a lineage tracing approach followed by Fluorescent-activated cell sorting, miRNA profiling of the FoxD1-derived cells not only comprehensively defined the transcriptional landscape of miRNAs that are critical for vascular development, but also identified key miRNAs that are likely to modulate the renal phenotype in its absence. These miRNAs include miRs‐10a, 18a, 19b, 24, 30c, 92a, 106a, 130a, 152, 181a, 214, 222, 302a, 370, and 381 that regulate Bcl2L11 (Bim) and miRs‐15b, 18a, 21, 30c, 92a, 106a, 125b‐5p, 145, 214, 222, 296‐5p and 302a that regulate p53-effector genes. Consistent with the profiling results, ectopic apoptosis was observed in the cellular derivatives of the FoxD1 derived progenitor lineage and reiterates the importance of renal stromal miRNAs in cellular homeostasis.[194]

Nervous system

miRNAs appear to regulate the development and function of the nervous system.[195] Neural miRNAs are involved at various stages of synaptic development, including dendritogenesis (involving miR-132, miR-134 and miR-124), synapse formation[196] and synapse maturation (where miR-134 and miR-138 are thought to be involved).[197] Elimination of miRNA formation in mice by experimental silencing of Dicer has led to pathological outcomes, such as reduced neuronal size and motor abnormalities when silenced in striatal neurons[198] and neurodegeneration when silenced in forebrain neurons.[199] Some studies find altered miRNA expression in Alzheimer's disease,[200] as well as schizophrenia, bipolar disorder, major depression and anxiety disorders.[201][202][203]

Stroke

A Center for Disease Control and Prevention szerint a stroke az egyik vezető halál- és hosszútávúfogyaték-ok Amerikában. Az esetek 87%-a ischaemiás, mely az agyi artéria okklúziójából ered. Így az agy nem jut elég tápanyaghoz, például oxigénhez és glükózhoz, és nem távoznak onnan a fölös anyagok, például a szén-dioxid.[204][205] A miRNS-ek a cerebralis ischaemia patogenezisében lévő, például a gyulladásban, az angiogenezisben és az apoptózisban fontos gének poszttranszlációs csendesítésével működnek.[206] 

Függőség

The vital role of miRNAs in gene expression is significant to addiction, specifically alcoholism.[207] Chronic alcohol abuse results in persistent changes in brain function mediated in part by alterations in gene expression.[207] miRNA global regulation of many downstream genes deems significant regarding the reorganization or synaptic connections or long term neural adaptations involving the behavioral change from alcohol consumption to withdrawal and/or dependence.[208] Up to 35 different miRNAs have been found to be altered in the alcoholic post-mortem brain, all of which target genes that include the regulation of the cell cycle, apoptosis, cell adhesion, nervous system development and cell signaling.[207] Altered miRNA levels were found in the medial prefrontal cortex of alcohol-dependent mice, suggesting the role of miRNA in orchestrating translational imbalances and the creation of differentially expressed proteins within an area of the brain where complex cognitive behavior and decision making likely originate.[209]

miRNAs can be either upregulated or downregulated in response to chronic alcohol use. miR-206 expression increased in the prefrontal cortex of alcohol-dependent rats, targeting the transcription factor brain-derived neurotrophic factor (BDNF) and ultimately reducing its expression. BDNF plays a critical role in the formation and maturation of new neurons and synapses, suggesting a possible implication in synapse growth/synaptic plasticity in alcohol abusers.[210] miR-155, important in regulating alcohol-induced neuroinflammation responses, was found to be upregulated, suggesting the role of microglia and inflammatory cytokines in alcohol pathophysiology.[211] Downregulation of miR-382 was found in the nucleus accumbens, a structure in the basal forebrain significant in regulating feelings of reward that power motivational habits. miR-382 is the target for the dopamine receptor D1 (DRD1), and its overexpression results in the upregulation of DRD1 and delta fosB, a transcription factor that activates a series of transcription events in the nucleus accumbens that ultimately result in addictive behaviors.[212] Alternatively, overexpressing miR-382 resulted in attenuated drinking and the inhibition of DRD1 and delta fosB upregulation in rat models of alcoholism, demonstrating the possibility of using miRNA-targeted pharmaceuticals in treatments.[212]

Obesitas

A miRNS-ek fontosak az őssejtprogenitorok zsírsejtté való differenciálódásának szabályzásában.[213] A pluripotens őssejtek adipogenezisben játszott szerepét a hMSC-Tert20 halhatatlanná tett csontvelő-eredetű stromalis sejtvonalban vizsgálták.[214] 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).[215] This paves the way for possible genetic obesity treatments.

További inzulinrezisztenciát, obesitast és diabéteszt csoportosító miRNS-osztály a let-7 család. Mennyisége az öregedés során nő.[216] A let-7 gyorsult öregedés mintájára történt ektópiás túlexpressziója egerekben inzulinrezisztenciát, így az obesitasnak és a diabétesznek való nagyobb kitettséget okozott.[217] Ezzel szemben a let-7 let-7-specifikus antagomirek injekciójával való inhibeálása nagyobb inzulinszenzitivitást és ellenállást okozott a nagyobb zsírtartalom miatti obesitasra és diabéteszre. Nemcsak gátolta az obesitas és a diabétesz kialakulását, hanem a meglévőt gyógyította.[218] Ezek alapján a let-7-gátlás új terápia lehet az obesitas és a 2-es típusú cukorbetegség ellen.

Homeosztázis

A miRNS-ek fontosak lehetnek a komplex enzimkaszkádok, például a hemosztatikus vérkoagulációs rendszer szabályzásában.[219] Funkcionális miRNS-eken végzett kísérletek 2018-ban a hemosztatikus rendszer terápiás céljait mutatták ki.[220][221] Ezek összefüggnek az endoplazmatikus retikulum kalciumhomeosztázisával, mely fontos a sejtdifferenciációhoz.[222]

Növényekben

A miRNS-ek számos fejlődési, homeosztatikus és immunfolyamat fontos szabályzói növényekben.[223] Céljuk a növényfejlődésben például a hajtások merisztémafejlődése, a levélnövekedés, a virág-, a magképzés vagy a gyökérnövekedés.[224][225][226][227] Továbbá összetett a szerepük számos hő-, alacsony hőmérsékleti, szárazság-, fénystresszel vagy γ-sugárzásnak való kitettséggel kapcsolatos abiotikus folyamatban.[223]

Vírusokban

A vírus-miRNS-ek fontosak a virális vagy gazdagének expressziójának a vírus javára való szabályzásában. Így a miRNS-ek fontosak a gazda-vírus kölcsönhatásokban és a vírusbetegségek patogenezisében.[228][229] A humán herpeszvírus-6 DNS-ének transzkripcióaktivátorainak expresszióját feltehetően vírus-miRNS-ek szabályozzák.[230]

Célelőrejelzés

A miRNS-ek fehérjekódoló gének cél-mRNS-eihez köthetnek, csökkentve transzlációjukat vagy lebontva azokat. Fontos pontos azonosításuk.[231] 18 in silico algoritmus összehasonlítása elérhető.[232] Funkcionális miRNS-célzó algoritmusok vizsgálata szerint sok funkcionális miRNS-t a célelőrejelző algoritmusok eltéveszthetnek.[220]

Jegyzetek

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