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===miRNA and heart disease===
===miRNA and heart disease===
The global role of miRNA function in the heart has been addressed by conditionally inhibiting miRNA maturation in the [[wikt:murine|murine]] heart, and has revealed that miRNAs play an essential role during its development.<ref>{{cite journal |author=Chen JF, Murchison EP, Tang R, ''et al.'' |title=Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=105 |issue=6 |pages=2111–6 |year=2008 |month=February |pmid=18256189 |pmc=2542870 |doi=10.1073/pnas.0710228105 |url=}}</ref><ref name="2007-Zhao">{{cite journal |author=Zhao Y, Ransom JF, Li A, ''et al.'' |title=Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2 |journal=Cell |volume=129 |issue=2 |pages=303–17 |year=2007 |month=April |pmid=17397913 |doi=10.1016/j.cell.2007.03.030 |url=}}</ref> miRNA expression profiling studies demonstrate that expression levels of specific miRNAs change in diseased human hearts, pointing to their involvement in cardiomyopathies.<ref>{{cite journal |author=Thum T, Galuppo P, Wolf C, ''et al.'' |title=MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure |journal=Circulation |volume=116 |issue=3 |pages=258–67 |year=2007 |month=July |pmid=17606841 |doi=10.1161/CIRCULATIONAHA.107.687947 |url=}}</ref><ref>{{cite journal |author=van Rooij E, Sutherland LB, Liu N, ''et al.'' |title=A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=48 |pages=18255–60 |year=2006 |month=November |pmid=17108080 |pmc=1838739 |doi=10.1073/pnas.0608791103 |url=}}</ref><ref>{{cite journal |author=Tatsuguchi M, Seok HY, Callis TE, ''et al.'' |title=Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy |journal=J. Mol. Cell. Cardiol. |volume=42 |issue=6 |pages=1137–41 |year=2007 |month=June |pmid=17498736 |pmc=1934409 |doi=10.1016/j.yjmcc.2007.04.004 |url=}}</ref> 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.<ref name="2007-Zhao"/><ref>{{cite journal |author=Zhao Y, Samal E, Srivastava D |title=Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis |journal=Nature |volume=436 |issue=7048 |pages=214–20 |year=2005 |month=July |pmid=15951802 |doi=10.1038/nature03817 |url=}}</ref><ref>{{cite journal |author=Xiao J, Luo X, Lin H, ''et al.'' |title=MicroRNA miR-133 represses HERG K+ channel expression contributing to QT prolongation in diabetic hearts |journal=J. Biol. Chem. |volume=282 |issue=17 |pages=12363–7 |year=2007 |month=April |pmid=17344217 |doi=10.1074/jbc.C700015200 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=17344217}}</ref><ref>{{cite journal |author=Yang B, Lin H, Xiao J, ''et al.'' |title=The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2 |journal=Nat. Med. |volume=13 |issue=4 |pages=486–91 |year=2007 |month=April |pmid=17401374 |doi=10.1038/nm1569}}</ref><ref>{{cite journal |author=Carè A, Catalucci D, Felicetti F, ''et al.'' |title=MicroRNA-133 controls cardiac hypertrophy |journal=Nat. Med. |volume=13 |issue=5 |pages=613–8 |year=2007 |month=May |pmid=17468766 |doi=10.1038/nm1582}}</ref><ref>{{cite journal |author=van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN |title=Control of stress-dependent cardiac growth and gene expression by a microRNA |journal=Science (journal) |volume=316 |issue=5824 |pages=575–9 |year=2007 |month=April |pmid=17379774 |doi=10.1126/science.1139089 |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=17379774}}</ref> In 2008, academic work on the relationship between miRNA and heart disease had advanced sufficiently to lead to the establishment of a company, '''miRagen Therapeutics'''<!-- redirect points to this section -->, with a primary focus on "cardiovascular health and disease".<ref name="2008-Glaser">{{cite news
The global role of miRNA function in the heart has been addressed by conditionally inhibiting miRNA maturation in the [[wikt:murine|murine]] heart, and has revealed that miRNAs play an essential role during its development.<ref>{{cite journal |author=Chen JF, Murchison EP, Tang R, ''et al.'' |title=Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=105 |issue=6 |pages=2111–6 |year=2008 |month=February |pmid=18256189 |pmc=2542870 |doi=10.1073/pnas.0710228105 |url=}}</ref><ref name="2007-Zhao">{{cite journal |author=Zhao Y, Ransom JF, Li A, ''et al.'' |title=Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2 |journal=Cell |volume=129 |issue=2 |pages=303–17 |year=2007 |month=April |pmid=17397913 |doi=10.1016/j.cell.2007.03.030 |url=}}</ref> miRNA expression profiling studies demonstrate that expression levels of specific miRNAs change in diseased human hearts, pointing to their involvement in cardiomyopathies.<ref>{{cite journal |author=Thum T, Galuppo P, Wolf C, ''et al.'' |title=MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure |journal=Circulation |volume=116 |issue=3 |pages=258–67 |year=2007 |month=July |pmid=17606841 |doi=10.1161/CIRCULATIONAHA.107.687947 |url=}}</ref><ref>{{cite journal |author=van Rooij E, Sutherland LB, Liu N, ''et al.'' |title=A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=48 |pages=18255–60 |year=2006 |month=November |pmid=17108080 |pmc=1838739 |doi=10.1073/pnas.0608791103 |url=}}</ref><ref>{{cite journal |author=Tatsuguchi M, Seok HY, Callis TE, ''et al.'' |title=Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy |journal=J. Mol. Cell. Cardiol. |volume=42 |issue=6 |pages=1137–41 |year=2007 |month=June |pmid=17498736 |pmc=1934409 |doi=10.1016/j.yjmcc.2007.04.004 |url=}}</ref> 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.<ref name="2007-Zhao"/><ref>{{cite journal |author=Zhao Y, Samal E, Srivastava D |title=Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis |journal=Nature |volume=436 |issue=7048 |pages=214–20 |year=2005 |month=July |pmid=15951802 |doi=10.1038/nature03817 |url=}}</ref><ref>{{cite journal |author=Xiao J, Luo X, Lin H, ''et al.'' |title=MicroRNA miR-133 represses HERG K+ channel expression contributing to QT prolongation in diabetic hearts |journal=J. Biol. Chem. |volume=282 |issue=17 |pages=12363–7 |year=2007 |month=April |pmid=17344217 |doi=10.1074/jbc.C700015200 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=17344217}}</ref><ref>{{cite journal |author=Yang B, Lin H, Xiao J, ''et al.'' |title=The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2 |journal=Nat. Med. |volume=13 |issue=4 |pages=486–91 |year=2007 |month=April |pmid=17401374 |doi=10.1038/nm1569}}</ref><ref>{{cite journal |author=Carè A, Catalucci D, Felicetti F, ''et al.'' |title=MicroRNA-133 controls cardiac hypertrophy |journal=Nat. Med. |volume=13 |issue=5 |pages=613–8 |year=2007 |month=May |pmid=17468766 |doi=10.1038/nm1582}}</ref><ref>{{cite journal |author=van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN |title=Control of stress-dependent cardiac growth and gene expression by a microRNA |journal=Science (journal) |volume=316 |issue=5824 |pages=575–9 |year=2007 |month=April |pmid=17379774 |doi=10.1126/science.1139089 |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=17379774}}</ref>
|author=Vicki Glaser |title=Tapping miRNA-Regulated Pathways |url=http://www.genengnews.com/articles/chitem.aspx?aid=2382
|work=Genetic Engineering & Biotechnology News |publisher=Mary Ann Liebert, Inc. |ppg=1, 50, 52&mdash;53 |date=2008-03-01 |accessdate=2008-05-16
}}</ref>


===Other conditions===
===Other conditions===

Revision as of 21:47, 1 April 2010

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


MicroRNAs are a class of post-transcriptional regulators [1] [2] [3] . They are short ~22 nucleotide RNA sequences that bind to complementary sequences in the 3’ UTR of multiple target mRNAs, usually resulting in their silencing [4] . MicroRNAs target ~60% of all genes [5] , are abundantly present in all human cells [6] and are able to repress hundreds of targets each [7][8]. These features, coupled with their conservation in organisms ranging from the unicellular algae Chlamydomonas reinhardtii [9] to mitochondria [10], suggest they are a vital part of genetic regulation with ancient origins [11].


MicroRNAs were first discovered in 1993 by Victor Ambros, Rosalind Lee and Rhonda Feinbaum during a study into development in the nematode C. elegans regarding the gene lin-14 [12]. This screen led to the discovery that the lin-14 was able to be regulated by a short RNA product from lin-4, a gene that transcribed a 61 nucleotide precursor that matured to a 22 nucleotide mature RNA which contained sequences partially complementary to multiple sequences in the 3’ UTR of the lin-14 mRNA. This complementarity was sufficient and necessary to inhibit the translation of lin-14 mRNA. Retrospectively, this was the first microRNA to be identified, though at the time Ambros et al speculated it to be a nematode idiosyncrasy. It was only in 2000 when let-7 was discovered to repress lin-41, lin-14, lin28, lin42 and daf12 mRNA during transition in developmental stages in C. elegans and that this function was phylogenetically conserved in species beyond nematodes [13] [14], that it became apparent the short non-coding RNA identified in 1993 was part of a wider phenomenon. Since then over 10,000 miRNAs have been discovered in all studied multicellular eukaryotes including mammals, fungi and plants. More than 700 miRNAs have so far been identified in humans [15] and over 800 more are predicted to exist. [16]. Comparing miRNAs between species can even be used to delineate molecular evolutionary history [17] on the basis that the complexity of an organism's phenotype may reflect that of the microRNA found in the genotype [18] .


When the human genome project mapped its first chromosome in 1999, it was predicted it would contain over 100,000 protein coding genes. However, only around 20,000 were eventually identified (International Human Genome Sequencing Consortium, 2004) and for a long time much of the non-protein-coding DNA was considered "junk", though conventional wisdom holds that much if not most of the genome is functional [19]. Since then, the advent of sophisticated bioinformatics approaches combined with genome tiling studies examining the transcriptome [20], systematic sequencing of full length cDNA libraries [21] and experimental validation [22] (including the creation of miRNA derived antisense oligonucleotides called antagomirs) have revealed that many transcripts are for non protein coding RNA of which many new classes have been deducted such as snoRNA and miRNA [23] . Unfortunately, the rate of validation of microRNA targets is substantially more time consuming than that of predicting sequences and targets.

Due to their abundant presence and far-reaching potential, miRNAs have all sorts of functions in physiology, from cell differentiation, proliferation, apoptosis [24] to the endocrine system [25] [26], haematopoiesis [27], fat metabolism [28], limb morphogenesis [29] . They display different expression profiles from tissue to tissue [30] , reflecting the diversity in cellular phenotypes and as such suggest a role in tissue differentiation and maintenance [31] [32].

Nomenclature

Since hundreds of human miRNAs and thousands across other species, a system of nomenclature has been adopted and names are designated to specific miRNAs before publication of their discovery;[33][34] Experimentally confirmed microRNAs are given a number that is attached to the prefix mir followed by a dash eg mir-123. The uncapitalised mir- refers to the pre-miRNA and the capitalised miR- refers to the mature form. miRNAs with similar structures bar at 1 or 2 nucleotides are annotated to show their similar structure with added lower case letter eg miR-1a and miR-1b. It is possible for miRNAs at different loci to produce the same miRNA and these are show with additional number eg miR-1-1 and miR-1-2. Strictly speaking, microRNA nomenclature should also be preceded by the annotation for the species they are observed in eg homo sapiens = hsa-miR-xxx. Other common miRNA species include viral v-mirNA and drosphila d-miRNA. microRNAs originating for the 3’ end or 5’ end are denoted with a -3p or 5p suffix eg. miR-142-5p, miR-142-3p.

Biogenesis

MicroRNAs are produced from either their own genes or from introns

Most microRNA genes are found in intergenic regions or in anti-sense oritentation to certain genes [35] and as such contain their own miRNA gene promoter and regulatory units [36] [37] [38] [39]. However, as much as 40% are said to lie in the introns of protein and non-protein coding genes or even rarely in exons [40] . These are usually, though not exclusively, found in a sense orientation [41] [42] and thus usually show a concurrent transcription and regulation expression profile originating from a common promoter with their host genes [43] [44] [45] . Other microRNA genes showing a common promoter include the 42-48% of all miRNAs originating from polycistronic units contaning 2-7 discrete loops from which mature miRNAs are processed [46] [47], though 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 class II (meaning transcribed by POL II) genes such as protein coding genes [48] [49]. 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 to those encoded by their DNA. This increases the diversity and scope of miRNA action beyond that implicated from the genome alone.

microRNA gene transcription via POL II or POL III

In the nucleus, polymerase II (POL II) is usually used to transcribe microRNA encoding parts of the genome [50] [51] often through binding to a promoter found near the sequence destined to be the hairpin loop of the pre-miRNA. This produces a transcript that is capped at the 5’ end, polyadenylated to give a (poly)A tail [52] [53] and spliced to form pri-miRNA several hundred to thousand bp in size [54] [55]. Curiously, some pri-miRNAs have been shown to be able to co-ordinately express both miRNAs and mRNAs, when the stem loop precursor is found in the 3’ UTR of an mRNA [56]. Uncommonly, polymerase III (POL III) is speculated to be used instead of POL II when transcribing microRNA that have upstream -Alu, -tRNA, mammalian wide interspersed repeat (MWIR) promoter units [57].

Pri-miRNA are processed by the microprocessor complex consisting of drosha and its cofactor DGCR8 into pre-miRNAs.

Pri-miRNA contains at least 1 (up to 6 when transcribed from polycistronic units) ~70 nucleotide hairpin loop structures, there is a potential for a single pri-miRNA to house many miRNAs (Altuvia et al., 2005). The hairpin loops have >40 nucleotide flanking RNA sequences necessary for efficient processing (Zeng and Cullen, 2005). These are recognised by the DiGeorge Syndrome Critical Region 8 (DGCR8), the cofactor to drosha, (Han et al., 2006). DGCR8 is a dsRNA binding nuclear protein that recognizes the hairpin loop of the pri-miRNA and orientates the catalytic RNAse III domain of drosha for cleavage (Han et al., 2004). This cleavage occurs around 11 nucleotides from their base (2 helical RNA turns into the stem)(Zeng et al., 2005) by Drosha, a RNAse III type dsRNA specific endonuclease, to form pre-miRNA (Lee et al., 2003)(47,48,49,50). Together, drosha and DGCR8 (the invertebrate equivalent is Pasha (Landthaler et al., 2004)) form the microprocessor complex (Denli et al., 2004; Gregory et al., 2004). The microprocessor complex introduces staggered cuts to the ends of the hairpin loop arms resulting in a 2 nucleotide overhand on the 3’ end and phosphate on the 5’ end (Denli et al., 2004) to produce a pre-miRNA of ~ 70 nt in length (Denli et al., 2004; Gregory et al., 2004; Han et al., 2004; Han et al., 2006; Landthaler et al., 2004; Lee et al., 2003; Zeng and Cullen, 2005; Zeng et al., 2005). Mostly, one arm of the hairpin loop is destined to become the mature miRNA, though rarely a mature miRNA may be produced from either arm eg Mir-458-3p/mir-458-5p and mir-202/mir-202* with the asterisk applying to less predominantly expressed transcript.

There is evidence that pre-miRNAs can be produced without having to undergo the microprocessor machinery if they are directly spliced from the introns in which they reside (Okamura et al., 2007; Ruby et al., 2007). These miRNAs are called mirtrons and have traditionally been thought to only exist in drosphila and C. elegans. Recently however, mammalian mirtons that even show conservation between species have recently been discovered (Berezikov et al., 2007).

Pri-miRNA can also be subject to RNA editing wherein the miRNA processing or specificity is altered through adenosine deaminase acting on RNA (ADAR) enzymes catalysing adenosine to inosine transitions, the most common form of RNA editing in metazoans (Valente and Nishikura, 2005). RNA editing has been shown to occur in 6% of miRNAs (Blow et al., 2006), even altering the specificity of miRNAs when it was observed in the seed region of miR-376, though this is only present in the CNS (Kawahara et al., 2007). RNA editing of microRNA can also prevent their processing, as seen in the pri-miR-142 editing leading to degradation by the tudor SN protein (a RISC component) and thus avoiding of the drosha pathway (Yang et al., 2006). Overall, this offers many implications in expanding the already complicated role in genetic expression that are covered in more detail than this paper has the opportunity to do in an excellent review (Ohman, 2007).

pre-miRNA is exported from nucleus to cytoplasm by exportin 5

The nuclear membrane protein exportin 5 recognises the 2 nucleotide overhang on the 3 * end of the pre-miRNA (Zeng and Cullen, 2004) and then transports it into the cytoplasm using ran-guanine triphosphatase (Ran-GTP) (Bohnsack et al., 2004) (Yi et al., 2003) (Yi et al., 2003).

Dicer cleavage, cofactor binding and RISC formation

In the cytoplasm the pre-miRNA is cleaved by another RNAse III type double stranded endonuclease called Dicer (Bernstein et al., 2001; Hutvagner et al., 2001; Ketting et al., 2001). Dicer cleavage of pre-miRNA results in an imperfect miRNA:miRNA* duplex around 20-25 nucleotides in size (Hutvagner et al., 2001; Ketting et al., 2001) containing the mature miRNA strand and its opposite complementary miRNA* strand (Lim et al., 2003)(Schwarz et al., 2003). Dicer is associated with the cofactors immunodeficiency virus (HIV) transactivating response RNA binding protein (TRBP)(Chendrimada et al., 2005; Haase et al., 2005) and protein activator of the interferon induced protein kinase PACT (Lee et al., 2006) that physically bring the TRBP-PACT-dicer complex into contact with Ago2 (Kok et al., 2007) to form the RNA Induced Silencing (RISC) loading apparatus. Dicer processing of the pre-miRNA is thought to be coupled to the unwinding of the duplex to produce a mature miRNA which Ago2 binds to, forming the active miRISC complex (Maniataki and Mourelatos, 2005). The mature miRNA then guides the RISC to target sites in order to induce silencing (Gregory et al., 2005; Martinez et al., 2002). The precise sequence of events is difficult to elucidate and still under debate (MacRae et al., 2008).

Generally, only 1 strand of the miRNA duplex is incorporated into the miRISC and is selected on the basis of it being less stable thermodynamically and capable of weaker base-pairing than the other strand (Krol et al., 2004)(Khvorova et al., 2003; Schwarz et al., 2003), though the position of the stem-loop within the pre-miRNA has been implicated (Lin et al., 2005). The other strand, called the passenger strand due to its lower levels in the steady state, is denoted by miRNA* (Lau et al., 2001). In short interfering RNAs (siRNAs- see below) it is often cleaved and degraded by the argonaute protein Ago2 in the RISC in order to integrate the guide strand into the RISC, but this is not necessary in miRNAs (Matranga et al., 2005) (Rand et al., 2005). The passenger strand is normally degraded and present in lower levels in cells in the steady state, though there have been instances where both strands of the duplex have been viable and become functional miRNA that target different mRNA populations (Okamura et al., 2008). However, there is also evidence that the duplex as a whole is incorporated and operates in a Fragile X Mental Retardation Protein (FMRP- see below) mediated strand-exchange system with the target mRNA during miRNA:mRNA assembly (Plante and Provost, 2006).

Homo sapiens has 8 argonaute proteins divided into 2 families based on sequence similarities: AGO (present in all mammalian cells and called E1F2C/hAgo in humans) and PIWI (conserved to the germ line and hematopoietic stem cells) (Sasaki et al., 2003; Sharma et al., 2001). In humans, RISC is composed of Ago family members 1-4 amongst other proteins, which seem to ultimately affect the outcome of miRISC:target binding (Hammond et al., 2001) (Meister et al., 2004). Ago proteins contain 2 conserved RNA binding domains: a PAZ domain that can bind the single stranded 3’ end of the microRNA and a PIWI domain that structurally resembles ribonuclease-H and functions to interact with the 5’ end of the guide strand (Lingel and Sattler, 2005). It is important to note that out of the 4 mammalian argonaute proteins, only Ago2 has endonucleolytic (also known as slicer) ability and is the only argonaute necessary for RNA silencing, though the others are involved in translational repression (Meister et al., 2004).

There are other proteins found in the miRISC, also referred to as the miRNP complex (Mourelatos et al., 2002), that are associated with the AGOs but as yet not fully characterised (94) and are thought to modulate the silencing effects of the miRISC (MacRae et al., 2008). They are covered in detail in other excellent review papers (MacRae et al., 2008; Mourelatos et al., 2002), though I include here a few that have been mentioned and will be discussed later on in more detail: the SMN complex (Mourelatos et al., 2002), fragile X mental retardation protein (FMRP) (Caudy et al., 2002; O'Donnell and Warren, 2002), tudor staphylococcal nuclease-domain-containing protein (tudor-SN) (Yang et al., 2006).

Turnover of mature microRNAs

miRNA biogenesis is highly regulated. It is controlled at both transcriptional and post-transcriptional levels. Overexpression and underexpression are linked to various human diseases, especially cancers. An additional layer of regulation of animal miRNA activity is important for rapid changes of miRNA expression profiles. Degradation of mature miRNAs is mediated by the 5´-->3´ exoribonuclease XRN2.[58]

Cellular functions

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.[59] Perfect or near perfect base pairing with the target RNA promotes cleavage of the RNA.[60] This is the primary mode of plant microRNAs.[61] In animals, microRNAs more often only partially base pair and inhibit protein translation of the target mRNA[62] (this exists in plants as well but is less common).[61] MicroRNAs that are partially complementary to the target can also speed up deadenylation, causing mRNAs to be degraded sooner.[63] For partially complementary microRNA to recognise their targets, the nucleotides 2–7 of the miRNA ('seed region'), still have to be perfectly complementary.[64] miRNAs occasionally also causes DNA methylation of promoter sites and therefore affecting the expression of targeted genes.[65][66] miRNAs function in association with a complement of proteins collectively termed the miRNP. Human miRNPs contain eIF2C2 (also known as Argonaute 2), DDX20, GEMIN4 and microRNA.[67]

Animal microRNAs target in particular developmental genes. In contrast, genes involved in functions common to all cells, such as gene expression, have very few microRNA target sites and seem to be under selection to avoid targeting by microRNAs.[68]

This effect was first described for the worm C. elegans in 1993 by Victor Ambros and coworkers.[69] As of 2002, miRNAs have been confirmed in various plants and animals, including C. elegans, human and the plant Arabidopsis thaliana. Work at the University of Louisville has resulted in the production of microarrays dubbed MMChips containing all then known miRNAs for human, mouse, rat, dog, C. elegans and Drosophila.[70] Agilent has subsequently commercialized a human miRNA microarray.[71]

Mirtrons are the type of microRNAs which are located in the introns of the mRNA encoding host genes. All the miRNAs in plants are derived from the sequential DCL1 cleavages from pri-miRNA to give pre-miRNA (or miRNA precursor). But the mirtrons bypass the DCL1 cleavage and enter as pre-miRNA in the miRNA maturation pathway.

Gene activation

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),[72] but has also been demonstrated for endogenous microRNA.[73]

Experimental detection and manipulation of miRNA

MicroRNA expression can be quantified by modified RT-PCR followed by QPCR[74], or profiled against a database describing thousands of known miRNAs using microarray technology.[75] The activity of an miRNA can be experimentally inhibited using a locked nucleic acid oligo, a Morpholino oligo[76][77] or a 2'-O-methyl RNA oligo.[78] MicroRNA maturation can be inhibited at several points by steric-blocking oligos.[79] The miRNA target site of an mRNA transcript can also be blocked by a steric-blocking oligo[80][81]. Additionally, a specific miRNA can be silenced by a complementary antagomir.

Genomics of microRNA

It was initially thought that miRNA genes were located in intergenic regions, however, later study showed that several miRNA genes were located within introns of either protein-coding or noncoding genes, while only a few were located in exons of noncoding RNAs or UTR of protein coding genes. [82] Recently, it has been shown that miRNA genes overlap with the protein-coding region of the genes of a multigene family. [83]

miRNA and disease

Just as miRNA is involved in the normal functioning of eukaryotic cells, so has dysregulation of miRNA been associated with disease. Disease association in turn has led to increased funding opportunities for academic research and financial incentives for development and commercialization of miRNA-based diagnostics and therapeutics. After early commercialization aimed at academic research support was established, the initial research focus based on products and services requested was on cancer and neuroscience research. During 2007, interests indicated by product and services requested broadened to include cardiac research, virology, cell biology in general and plant biology.[70] A manually curated database miR2Disease that aims at documenting known relationships between miRNA dysregulation and human disease is publicly available. [84]

miRNA and cancer

Several miRNAs have been found to have links with some types of cancer.[85][86]

A study of mice altered to produce excess c-Myc — a protein 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.[87] Leukemia can be caused by the insertion of a virus next to the the 17-92 array of microRNAs leading to increased expression of this microRNA.[88]

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.[89]

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.[90] In 2008, the companies Asuragen and Exiqon were working to commercialize this potential for miRNAs to act as cancer biomarkers.[70][91]

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.[92][93] miRNA expression profiling studies demonstrate that expression levels of specific miRNAs change in diseased human hearts, pointing to their involvement in cardiomyopathies.[94][95][96] 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.[93][97][98][99][100][101]

Other conditions

One study implicates miRNA as a factor in the development of schizophrenia.[102]

References

  1. ^ Kusenda, B., Mraz, M., Mayer, J., and Pospisilova, S. (2006). MicroRNA biogenesis, functionality and cancer relevance. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 150, 205-215.
  2. ^ Place, R. F., Li, L. C., Pookot, D., Noonan, E. J., and Dahiya, R. (2008). MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci U S A 105, 1608-1613.
  3. ^ Vasudevan, S., Tong, Y., and Steitz, J. A. (2007). Switching from repression to activation: microRNAs can up-regulate translation. Science 318, 1931-1934.
  4. ^ Bartel, D. P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281-297.
  5. ^ Friedman, R. C., Farh, K. K., Burge, C. B., and Bartel, D. P. (2009). Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19, 92-105.
  6. ^ Lim, L. P., Lau, N. C., Weinstein, E. G., Abdelhakim, A., Yekta, S., Rhoades, M. W., Burge, C. B., and Bartel, D. P. (2003). The microRNAs of Caenorhabditis elegans. Genes Dev 17, 991-1008.
  7. ^ Brennecke, J., Stark, A., Russell, R. B., and Cohen, S. M. (2005). Principles of microRNA-target recognition. PLoS Biol 3, e85.
  8. ^ Lim, L. P., Lau, N. C., Garrett-Engele, P., Grimson, A., Schelter, J. M., Castle, J., Bartel, D. P., Linsley, P. S., and Johnson, J. M. (2005). Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769-773.
  9. ^ Molnar, A., Schwach, F., Studholme, D. J., Thuenemann, E. C., and Baulcombe, D. C. (2007). miRNAs control gene expression in the single-cell alga Chlamydomonas reinhardtii. Nature 447, 1126-1129.
  10. ^ Kren, B. T., Wong, P. Y., Sarver, A., Zhang, X., Zeng, Y., and Steer, C. J. (2009). microRNAs identified in highly purified liver-derived mitochondria may play a role in apoptosis. RNA Biol 6.
  11. ^ Grosshans, H., and Slack, F. J. (2002). Micro-RNAs: small is plentiful. J Cell Biol 156, 17-21.
  12. ^ 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.
  13. ^ Reinhart, B. J., Slack, F. J., Basson, M., Pasquinelli, A. E., Bettinger, J. C., Rougvie, A. E., Horvitz, H. R., and Ruvkun, G. (2000). The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901-906.
  14. ^ Pasquinelli, A. E., Reinhart, B. J., Slack, F., Martindale, M. Q., Kuroda, M. I., Maller, B., Hayward, D. C., Ball, E. E., Degnan, B., Muller, P., et al. (2000). Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408, 86-89.
  15. ^ Homo sapiens miRNAs in the miRBase at Manchester University
  16. ^ Bentwich, I., Avniel, A., Karov, Y., Aharonov, R., Gilad, S., Barad, O., Barzilai, A., Einat, P., Einav, U., Meiri, E., et al. (2005). Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet 37, 766-770.
  17. ^ Tanzer, A., and Stadler, P. F. (2004). Molecular evolution of a microRNA cluster. J Mol Biol 339, 327-335.
  18. ^ Lee, C. T., Risom, T., and Strauss, W. M. (2007a). Evolutionary conservation of microRNA regulatory circuits: an examination of microRNA gene complexity and conserved microRNA-target interactions through metazoan phylogeny. DNA Cell Biol 26, 209-218.
  19. ^ Pheasant, M., and Mattick, J. S. (2007). Raising the estimate of functional human sequences. Genome Res 17, 1245-1253.
  20. ^ Bertone, P., Stolc, V., Royce, T. E., Rozowsky, J. S., Urban, A. E., Zhu, X., Rinn, J. L., Tongprasit, W., Samanta, M., Weissman, S., et al. (2004). Global identification of human transcribed sequences with genome tiling arrays. Science 306, 2242-2246.
  21. ^ Ota, T., Suzuki, Y., Nishikawa, T., Otsuki, T., Sugiyama, T., Irie, R., Wakamatsu, A., Hayashi, K., Sato, H., Nagai, K., et al. (2004b). Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet 36, 40-45.
  22. ^ Kuhn, D. E., Martin, M. M., Feldman, D. S., Terry, A. V., Jr., Nuovo, G. J., and Elton, T. S. (2008). Experimental validation of miRNA targets. Methods 44, 47-54.
  23. ^ Huttenhofer, A., Schattner, P., and Polacek, N. (2005). Non-coding RNAs: hope or hype? Trends Genet 21, 289-297.
  24. ^ Brennecke, J., Hipfner, D. R., Stark, A., Russell, R. B., and Cohen, S. M. (2003). bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113, 25-36.
  25. ^ Cuellar, T. L., and McManus, M. T. (2005). MicroRNAs and endocrine biology. J Endocrinol 187, 327-332.
  26. ^ Poy, M. N., Eliasson, L., Krutzfeldt, J., Kuwajima, S., Ma, X., Macdonald, P. E., Pfeffer, S., Tuschl, T., Rajewsky, N., Rorsman, P., and Stoffel, M. (2004). A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432, 226-230.
  27. ^ Chen, C. Z., Li, L., Lodish, H. F., and Bartel, D. P. (2004). MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83-86.
  28. ^ Wilfred, B. R., Wang, W. X., and Nelson, P. T. (2007). Energizing miRNA research: a review of the role of miRNAs in lipid metabolism, with a prediction that miR-103/107 regulates human metabolic pathways. Mol Genet Metab 91, 209-217.
  29. ^ Harfe, B. D., McManus, M. T., Mansfield, J. H., Hornstein, E., and Tabin, C. J. (2005). The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb. Proc Natl Acad Sci U S A 102, 10898-10903.
  30. ^ Lagos-Quintana, M., Rauhut, R., Yalcin, A., Meyer, J., Lendeckel, W., and Tuschl, T. (2002). Identification of tissue-specific microRNAs from mouse. Curr Biol 12, 735-739.
  31. ^ Lim, L. P., Lau, N. C., Garrett-Engele, P., Grimson, A., Schelter, J. M., Castle, J., Bartel, D. P., Linsley, P. S., and Johnson, J. M. (2005). Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769-773.
  32. ^ Lagos-Quintana, M., Rauhut, R., Meyer, J., Borkhardt, A., and Tuschl, T. (2003). New microRNAs from mouse and human. Rna 9, 175-179.
  33. ^ Ambros, V., Bartel, B., Bartel, D. P., Burge, C. B., Carrington, J. C., Chen, X., Dreyfuss, G., Eddy, S. R., Griffiths-Jones, S., Marshall, M., et al. (2003). A uniform system for microRNA annotation. Rna 9, 277-279.
  34. ^ Griffiths-Jones, S., Grocock, R. J., van Dongen, S., Bateman, A., and Enright, A. J. (2006). miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 34, D140-144.
  35. ^ Lau, N. C., Lim, L. P., Weinstein, E. G., and Bartel, D. P. (2001). An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294, 858-862.
  36. ^ Lau, N. C., Lim, L. P., Weinstein, E. G., and Bartel, D. P. (2001). An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294, 858-862.
  37. ^ Lee, Y., Kim, M., Han, J., Yeom, K. H., Lee, S., Baek, S. H., and Kim, V. N. (2004). MicroRNA genes are transcribed by RNA polymerase II. Embo J 23, 4051-4060.
  38. ^ Lagos-Quintana, M., Rauhut, R., Lendeckel, W., and Tuschl, T. (2001). Identification of novel genes coding for small expressed RNAs. Science 294, 853-858.
  39. ^ Lee, R. C., and Ambros, V. (2001). An extensive class of small RNAs in Caenorhabditis elegans. Science 294, 862-864.. An extensive class of small RNAs in Caenorhabditis elegans. Science 294, 862-864.
  40. ^ Rodriguez, A., Griffiths-Jones, S., Ashurst, J. L., and Bradley, A. (2004). Identification of mammalian microRNA host genes and transcription units. Genome Res 14, 1902-1910.
  41. ^ Cai, X., Hagedorn, C. H., and Cullen, B. R. (2004). Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. Rna 10, 1957-1966.
  42. ^ Weber, M. J. (2005). New human and mouse microRNA genes found by homology search. Febs J 272, 59-73.
  43. ^ Kim, Y. K., and Kim, V. N. (2007). Processing of intronic microRNAs. Embo J 26, 775-783.
  44. ^ Baskerville, S., and Bartel, D. P. (2005). Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. Rna 11, 241-247.
  45. ^ Rodriguez, A., Griffiths-Jones, S., Ashurst, J. L., and Bradley, A. (2004). Identification of mammalian microRNA host genes and transcription units. Genome Res 14, 1902-1910.
  46. ^ Altuvia, Y., Landgraf, P., Lithwick, G., Elefant, N., Pfeffer, S., Aravin, A., Brownstein, M. J., Tuschl, T., and Margalit, H. (2005). Clustering and conservation patterns of human microRNAs. Nucleic Acids Res 33, 2697-2706.
  47. ^ Lee, Y., Jeon, K., Lee, J. T., Kim, S., and Kim, V. N. (2002). MicroRNA maturation: stepwise processing and subcellular localization. Embo J 21, 4663-4670.
  48. ^ Lee, Y., Kim, M., Han, J., Yeom, K. H., Lee, S., Baek, S. H., and Kim, V. N. (2004). MicroRNA genes are transcribed by RNA polymerase II. Embo J 23, 4051-4060.
  49. ^ Zhou, X., Ruan, J., Wang, G., and Zhang, W. (2007). Characterization and identification of microRNA core promoters in four model species. PLoS Comput Biol 3, e37.
  50. ^ Lee, Y., Kim, M., Han, J., Yeom, K. H., Lee, S., Baek, S. H., and Kim, V. N. (2004). MicroRNA genes are transcribed by RNA polymerase II. Embo J 23, 4051-4060.
  51. ^ Zhou, X., Ruan, J., Wang, G., and Zhang, W. (2007). Characterization and identification of microRNA core promoters in four model species. PLoS Comput Biol 3, e37.
  52. ^ Cai, X., Hagedorn, C. H., and Cullen, B. R. (2004). Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. Rna 10, 1957-1966.
  53. ^ Lee, Y., Kim, M., Han, J., Yeom, K. H., Lee, S., Baek, S. H., and Kim, V. N. (2004). MicroRNA genes are transcribed by RNA polymerase II. Embo J 23, 4051-4060.
  54. ^ Cai, X., Hagedorn, C. H., and Cullen, B. R. (2004). Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. Rna 10, 1957-1966.
  55. ^ Lee, Y., Jeon, K., Lee, J. T., Kim, S., and Kim, V. N. (2002). MicroRNA maturation: stepwise processing and subcellular localization. Embo J 21, 4663-4670.
  56. ^ Cai, X., Hagedorn, C. H., and Cullen, B. R. (2004). Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. Rna 10, 1957-1966.
  57. ^ Borchert, G. M., Lanier, W., and Davidson, B. L. (2006). RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol 13, 1097-1101
  58. ^ Chatterjee S, Großhans H (2009). "Active turnover modulates mature microRNA activity in Caenorhabditis elegans". Nature. 461: 546–459. doi:10.1038/nature08349. {{cite journal}}: Unknown parameter |month= ignored (help)
  59. ^ Wang XJ, Reyes JL, Chua NH, Gaasterland T (2004). "Prediction and identification of Arabidopsis thaliana microRNAs and their mRNA targets". Genome Biol. 5 (9): R65. doi:10.1186/gb-2004-5-9-r65. PMC 522872. PMID 15345049.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  60. ^ Kawasaki H, Taira K (2004). "MicroRNA-196 inhibits HOXB8 expression in myeloid differentiation of HL60 cells". Nucleic Acids Symp Ser. 48 (48): 211–2. doi:10.1093/nass/48.1.211. PMID 17150553.
  61. ^ a b Moxon S, Jing R, Szittya G; et al. (2008). "Deep sequencing of tomato short RNAs identifies microRNAs targeting genes involved in fruit ripening". Genome Res. 18 (10): 1602–9. doi:10.1101/gr.080127.108. PMC 2556272. PMID 18653800. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  62. ^ Williams AE (2008). "Functional aspects of animal microRNAs". Cell. Mol. Life Sci. 65 (4): 545–62. doi:10.1007/s00018-007-7355-9. PMID 17965831. {{cite journal}}: Unknown parameter |month= ignored (help)
  63. ^ Eulalio A, Huntzinger E, Nishihara T, Rehwinkel J, Fauser M, Izaurralde E (2009). "Deadenylation is a widespread effect of miRNA regulation". RNA. 15 (1): 21–32. doi:10.1261/rna.1399509. PMC 2612776. PMID 19029310. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  64. ^ Mazière P, Enright AJ (2007). "Prediction of microRNA targets". Drug Discov. Today. 12 (11–12): 452–8. doi:10.1016/j.drudis.2007.04.002. PMID 17532529. {{cite journal}}: Unknown parameter |month= ignored (help)
  65. ^ Tan Y, Zhang B, Wu T; et al. (2009). "Transcriptional inhibition of Hoxd4 expression by noncoding RNAs in human breast cancer cells". BMC Mol. Biol. 10 (1): 12. doi:10.1186/1471-2199-10-12. PMC 2680403. PMID 19232136. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  66. ^ Hawkins PG, Morris KV (2008). "RNA and transcriptional modulation of gene expression". Cell Cycle. 7 (5): 602–7. PMID 18256543. {{cite journal}}: Unknown parameter |month= ignored (help)
  67. ^ Mourelatos Z, Dostie J, Paushkin S; et al. (2002). "miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs". Genes Dev. 16 (6): 720–8. doi:10.1101/gad.974702. PMC 155365. PMID 11914277. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  68. ^ Stark A, Brennecke J, Bushati N, Russell RB, Cohen SM (2005). "Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3'UTR evolution". Cell. 123 (6): 1133–46. doi:10.1016/j.cell.2005.11.023. PMID 16337999.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  69. ^ 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): 843–54. doi:10.1016/0092-8674(93)90529-Y. PMID 8252621. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  70. ^ a b c Cite error: The named reference 2008-Glaser was invoked but never defined (see the help page).
  71. ^ staff (2007-06-15). "miRNA Detection Technology". Genetic Engineering & Biotechnology News. Mary Ann Liebert, Inc. p. 30. {{cite news}}: |access-date= requires |url= (help); |format= requires |url= (help)
  72. ^ Li LC (2008). "Small RNA-Mediated Gene Activation". RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity. Caister Academic Press. ISBN 978-1-904455-25-7. {{cite book}}: External link in |chapterurl= (help); Unknown parameter |chapterurl= ignored (|chapter-url= suggested) (help)
  73. ^ Place RF, Li LC, Pookot D, Noonan EJ, Dahiya R (2008). "MicroRNA-373 induces expression of genes with complementary promoter sequences". Proc. Natl. Acad. Sci. U.S.A. 105 (5): 1608–13. doi:10.1073/pnas.0707594105. PMC 2234192. PMID 18227514.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  74. ^ Caifu, Chen (2005-10-25). "Real-time quantification of microRNAs by stem–loop RT–PCR". Nucleic Acids Research. 33 (20): e179. doi:10.1093/nar/gni178. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  75. ^ Jaclyn, Shingara (2005-07-25). "An optimized isolation and labeling platform for accurate microRNA expression profiling". RNA. 11 (9): 1461–1470. doi:10.1261/rna.2610405. PMC 1370829. PMID 16043497. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  76. ^ Kloosterman WP, Wienholds E, Ketting RF, Plasterk RH (2004). "Substrate requirements for let-7 function in the developing zebrafish embryo". Nucleic Acids Res. 32 (21): 6284–91. doi:10.1093/nar/gkh968. PMC 535676. PMID 15585662.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  77. ^ Flynt AS, Li N, Thatcher EJ, Solnica-Krezel L, Patton JG (2007). "Zebrafish miR-214 modulates Hedgehog signaling to specify muscle cell fate". Nat. Genet. 39 (2): 259–63. doi:10.1038/ng1953. PMID 17220889. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  78. ^ Meister G, Landthaler M, Dorsett Y, Tuschl T (2004). "Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing". RNA. 10 (3): 544–50. doi:10.1261/rna.5235104. PMC 1370948. PMID 14970398. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  79. ^ Kloosterman WP, Lagendijk AK, Ketting RF, Moulton JD, Plasterk RH (2007). "Targeted inhibition of miRNA maturation with morpholinos reveals a role for miR-375 in pancreatic islet development". PLoS Biol. 5 (8): e203. doi:10.1371/journal.pbio.0050203. PMC 1925136. PMID 17676975. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  80. ^ Choi, WY (2007). "Target Protectors Reveal Dampening and Balancing of Nodal Agonist and Antagonist by miR-430". Science. 318 (5848): 271–4. doi:10.1126/science.1147535. PMID 17761850. {{cite journal}}: |format= requires |url= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  81. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1038/nn2010, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1038/nn2010 instead.
  82. ^ Rodriguez A, Griffiths-Jones S, Ashurst JL, Bradley A (2004). "Identification of mammalian microRNA host genes and transcription units". Genome Res. 14 (10A): 1902–1910. doi:10.1101/gr.2722704. PMC 524413. PMID 15364901.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  83. ^ Das S (2009). "Evolutionary Origin and Genomic Organization of microRNA Genes in Immunoglobulin Lambda Variable Region Gene Family". Mol Biol Evol. 26 (5): 1179–1189. doi:10.1093/molbev/msp035. PMC 2727374. PMID 19246621.
  84. ^ Jiang Q, Wang Y, Hao Y, Juan L, Teng M, Zhang X, Li M, Wang G, Liu Y. (2009). "miR2Disease: a manually curated database for microRNA deregulation in human disease". Nucleic Acids Research. 37 (Database issue) (Database issue): D98–104. doi:10.1093/nar/gkn714. PMC 2686559. PMID 18927107. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  85. ^ He L, Thomson JM, Hemann MT; et al. (2005). "A microRNA polycistron as a potential human oncogene". Nature. 435 (7043): 828–33. doi:10.1038/nature03552. PMID 15944707. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  86. ^ Mraz M, Pospisilova S, Malinova K; et al. (2009). "MicroRNAs in chronic lymphocytic leukemia pathogenesis and disease subtypes". Leuk Lymphoma. 50 (3): 506–9. doi:10.1080/10428190902763517. PMID 19347736. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  87. ^ He L, Thomson JM, Hemann MT; et al. (2005). "A microRNA polycistron as a potential human oncogene". Nature. 435 (7043): 828–33. doi:10.1038/nature03552. PMID 15944707. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  88. ^ Cui JW, Li YJ, Sarkar A, Brown J, Tan YH, Premyslova M, Michaud C, Iscove N, Wang GJ, Ben-David Y. (2007). "Retroviral insertional activation of the Fli-3 locus in erythroleukemias encoding a cluster of microRNAs that convert Epo-induced differentiation to proliferation". Blood. 110 (7): 2631–40. doi:10.1182/blood-2006-10-053850. PMID 17586726. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  89. ^ O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT (2005). "c-Myc-regulated microRNAs modulate E2F1 expression". Nature. 435 (7043): 839–43. doi:10.1038/nature03677. PMID 15944709. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  90. ^ Lu J, Getz G, Miska EA; et al. (2005). "MicroRNA expression profiles classify human cancers". Nature. 435 (7043): 834–8. doi:10.1038/nature03702. PMID 15944708. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  91. ^ "Exiqon A/S To Acquire Oncotech" (Press release). BioSpace. 2007-11-27. Retrieved 2008-05-16. The transaction will create a world leader in molecular diagnostic products based on miRNA.
  92. ^ Chen JF, Murchison EP, Tang R; et al. (2008). "Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure". Proc. Natl. Acad. Sci. U.S.A. 105 (6): 2111–6. doi:10.1073/pnas.0710228105. PMC 2542870. PMID 18256189. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  93. ^ a b Zhao Y, Ransom JF, Li A; et al. (2007). "Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2". Cell. 129 (2): 303–17. doi:10.1016/j.cell.2007.03.030. PMID 17397913. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  94. ^ Thum T, Galuppo P, Wolf C; et al. (2007). "MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure". Circulation. 116 (3): 258–67. doi:10.1161/CIRCULATIONAHA.107.687947. PMID 17606841. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  95. ^ van Rooij E, Sutherland LB, Liu N; et al. (2006). "A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure". Proc. Natl. Acad. Sci. U.S.A. 103 (48): 18255–60. doi:10.1073/pnas.0608791103. PMC 1838739. PMID 17108080. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  96. ^ Tatsuguchi M, Seok HY, Callis TE; et al. (2007). "Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy". J. Mol. Cell. Cardiol. 42 (6): 1137–41. doi:10.1016/j.yjmcc.2007.04.004. PMC 1934409. PMID 17498736. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  97. ^ Zhao Y, Samal E, Srivastava D (2005). "Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis". Nature. 436 (7048): 214–20. doi:10.1038/nature03817. PMID 15951802. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  98. ^ Xiao J, Luo X, Lin H; et al. (2007). "MicroRNA miR-133 represses HERG K+ channel expression contributing to QT prolongation in diabetic hearts". J. Biol. Chem. 282 (17): 12363–7. doi:10.1074/jbc.C700015200. PMID 17344217. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  99. ^ Yang B, Lin H, Xiao J; et al. (2007). "The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2". Nat. Med. 13 (4): 486–91. doi:10.1038/nm1569. PMID 17401374. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  100. ^ Carè A, Catalucci D, Felicetti F; et al. (2007). "MicroRNA-133 controls cardiac hypertrophy". Nat. Med. 13 (5): 613–8. doi:10.1038/nm1582. PMID 17468766. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  101. ^ van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN (2007). "Control of stress-dependent cardiac growth and gene expression by a microRNA". Science (journal). 316 (5824): 575–9. doi:10.1126/science.1139089. PMID 17379774. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  102. ^ Evidence for X-chromosomal schizophrenia associated with microRNA alterations. Feng J, Sun G, Yan J, Noltner K, Li W, Buzin CH, Longmate J, Heston LL, Rossi J, Sommer SS. PLoS One. 2009 Jul 1;4(7):e6121. PMID 19568434

Further reading

See also

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