MicroRNA
From Wikipedia, the free encyclopedia
Jump to: navigation, search
The stem-loop secondary structure of a pre-microRNA from Brassica oleracea.
MicroRNAs (miRNAs) are post-transcriptional regulators that bind to complementary
sequences in the three prime untranslated regions (3' UTRs) of target messenger RNA
transcripts (mRNAs), usually resulting in gene silencing.[1][2] miRNAs are short
ribonucleic acid (RNA) molecules, on average only 22 nucleotides long. The human
genome may encode over 1000 miRNAs,[3][4] which may target about 60% of mammalian
genes[5] and are abundant in many human cell types.[6] Each miRNA may repress
hundreds of mRNAs.[7][8] MiRNAs are well conserved in eukaryotic organisms and are
thought to be a vital and evolutionarily ancient component of genetic
regulation.[9][10][11][12][13]
The first miRNAs were characterized in the early 1990s, but miRNAs were not
recognized as a distinct class of biologic regulators with conserved functions until the
early 2000s. Since then, miRNA research has revealed multiple roles in negative
regulation (transcript degradation and sequestering, translational suppression) and
possible involvement in positive regulation (transcriptional and translational activation).
By affecting gene regulation, miRNAs are likely to be involved in most biologic
processes.[14][15][16][17][18][19][20][21] Different sets of expressed miRNAs are found in
different cell types and tissues.[22]
Aberrant expression of miRNAs has been implicated in numerous disease states, and
miRNA-based therapies are under investigation.[23][24][25]
Contents
[hide]



1 History
2 Nomenclature
3 Biogenesis
o
o
o
o










3.1 Transcription
3.2 Nuclear processing
3.3 Nuclear export
3.4 Cytoplasmic processing
4 The RNA-induced silencing complex
5 Turnover of mature microRNAs
6 Cellular functions
7 Gene activation
8 Experimental detection and manipulation of miRNA
9 miRNA and disease
o 9.1 miRNA and cancer
o 9.2 miRNA and heart disease
o 9.3 Other conditions
10 miRNA and non-coding RNAs
11 References
o 11.1 Further reading
12 External links
13 See also
[edit] History
MicroRNAs were discovered in 1993 by Victor Ambros, Rosalind Lee and Rhonda
Feinbaum during a study of the gene lin-14 in the developmental processes of the
nematode C. elegans.[26] They found that lin-14 was regulated by a short RNA product
from lin-4. A 61 nucleotide precursor from the lin-4 gene matured to a 22 nucleotide
RNA containing 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 speculated that it was a nematode idiosyncrasy. Only in 2000
was let-7, which repressed lin-41, lin-14, lin28, lin42, and daf12 mRNA during
developmental stage transitions in C. elegans, found to be conserved in other
species.[27][28] indicating the existence of a wider phenomenon.
[edit] Nomenclature
Under a standard nomenclature system, names are assigned to experimentally confirmed
miRNAs before publication of their discovery.[29][30] The prefix "mir" is followed by a
dash and a number, the latter often indicating order of naming. For example, mir-123 was
named and likely discovered prior to mir-456. The uncapitalized "mir-" refers to the premiRNA, while a capitalized "miR-" refers to the mature form. miRNAs with nearly
identical sequences bar one or two nucleotides are annotated with an additional lower
case letter. For example, miR-123a would be closely related to miR-123b. miRNAs that
are 100% identical but are encoded at different places in the genome are indicated with
additional dash-number suffix: miR-123-1 and miR-123-2 are identical but are produced
from different pre-miRNAs. Species of origin is designated with a three-letter prefix, e.g.,
hsa-miR-123 would be from human (Homo sapiens) and oar-miR-123 would be a sheep
(Ovis aries) miRNA. Other common prefixes include 'v' for viral (miRNA encoded by a
viral genome) and 'd' for Drosophila miRNA (a fruit fly commonly studied in genetic
research). microRNAs originating from the 3’ or 5’ end of a pre-miRNA are denoted with
a -3p or -5p suffix. (In the past, this distinction was also made with 's' (sense) and 'as'
(antisense). When relative expression levels are known, an asterisk following the name
indicates an miRNA expressed at low levels relative to the miRNA in the opposite arm of
a hairpin. For example, miR-123 and miR-123* would share a pre-miRNA hairpin, but
relatively more miR-123 would be found in the cell.
[edit] Biogenesis
MicroRNAs are produced from either their own genes or from introns
Most microRNA genes are found in intergenic regions or in anti-sense orientation to
genes[31] and contain their own miRNA gene promoter and regulatory units.[31][32][33][34]
As much as 40% of miRNA genes may lie in the introns of protein and non-protein
coding genes or even in exons.[35] These are usually, though not exclusively, found in a
sense orientation [36][37] and thus usually are regulated together with their host
genes.[38][39][40] Other miRNA 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,[41][32] although this does not necessarily mean the mature
miRNAs of a family will be homologous in structure and function. The promoters
mentioned have been shown to have some similarities in their motifs to promoters of
other genes transcribed by RNA polymerase II such as protein coding genes.[32][42] The
DNA template is not the final word on mature miRNA production: 6% of human
miRNAs show RNA editing, the site-specific modification of RNA sequences to yield
products different from those encoded by their DNA. This increases the diversity and
scope of miRNA action beyond that implicated from the genome alone.
[edit] Transcription
miRNA genes are usually transcribed by RNA polymerase II (Pol II).[32][43] The
polymerase often binds to a promoter found near the DNA sequence encoding what will
become the hairpin loop of the pre-miRNA. The resulting transcript is capped with a
specially-modified nucleotide at the 5’ end, polyadenylated with multiple adenosines (a
poly(A) tail),[36][32] and spliced. The product, called a primary miRNA (pri-miRNA), may
be hundreds or thousands of nucleotides in length and contain one or more miRNA stem
loops.[36][32] When a stem loop precursor is found in the 3’ UTR, a transcript may serve as
a pri-miRNA and a mRNA.[36] RNA polymerase III (Pol III) transcribes some miRNAs,
especially those with upstream Alu sequences, transfer RNAs (tRNAs), and mammalian
wide interspersed repeat (MWIR) promoter units.[44]
[edit] Nuclear processing
A single pri-miRNA may contain from one to six miRNA precursors. These hairpin loop
structures are composed of about 70 nucleotides each. Each hairpin is flanked by
sequences necessary for efficient processing. The double-stranded RNA structure of the
hairpins in a pri-miRNA is recognized by a nuclear protein known as DiGeorge
Syndrome Critical Region 8 (DGCR8 or "Pasha" in invertebrates), named for its
association with DiGeorge Syndrome. DGCR8 associates with the enzyme Drosha, a
protein that cuts RNA, to form the "Microprocessor" complex.[45] In this complex,
DGCR8 orients the catalytic RNase III domain of Drosha to liberate hairpins from primiRNAs by cleaving RNA about eleven nucleotides from the hairpin base (two helical
RNA turns into the stem). The resulting hairpin, known as a pre-miRNA, has a twonucleotide overhang at its 3’ end; it has 3' hydroxyl and 5' phosphate groups.
pre-miRNAs that are spliced directly out of introns, bypassing the Microprocessor
complex, are known as "mirtrons." Originally thought to exist only in Drosophila and C.
elegans, mirtrons have now been found in mammals.[46]
Perhaps as many as 16% of pri-miRNAs may be altered through nuclear RNA
editing.[47][48][49] Most commonly, enzymes known as adenosine deaminases acting on
RNA (ADARs) catalyze adenosine to inosine (A to I) transitions. RNA editing can halt
nuclear processing (for example, of pri-miR-142, leading to degradation by the
ribonuclease Tudor-SN) and alter downstream processes including cytoplasmic miRNA
processing and target specificity (e.g., by changing the seed region of miR-376 in the
central nervous system).[47]
[edit] Nuclear export
pre-miRNA hairpins are exported from the nucleus in a process involving the
nucleocytoplasmic shuttle Exportin-5. This protein, a member of the karyopherin family,
recognizes a two-nucleotide overhang left by the RNase III enzyme Drosha at the 3' end
of the pre-miRNA hairpin. Exportin-5-mediated transport to the cytoplasm is energydependent, using GTP bound to the Ran protein.[50]
[edit] Cytoplasmic processing
In the cytoplasm, the pre-miRNA hairpin is cleaved by the RNase III enzyme Dicer.[51]
This endoribonuclease interacts with the 3' end of the hairpin and cuts away the loop
joining the 3' and 5' arms, yielding an imperfect miRNA:miRNA* duplex about 22
nucleotides in length.[51] Overall hairpin length and loop size influence the efficiency of
Dicer processing, and the imperfect nature of the miRNA:miRNA* pairing also affects
cleavage.[51][52] Although either strand of the duplex may potentially act as a functional
miRNA, only one strand is usually incorporated into the RNA-induced silencing complex
(RISC) where the miRNA and its mRNA target interact.
[edit] The RNA-induced silencing complex
The mature miRNA is part of an active RNA-induced silencing complex (RISC)
containing Dicer and many associated proteins.[53] RISC is also known as a microRNA
ribonucleoprotein complex (miRNP);[54] RISC with incorporated miRNA is sometimes
referred to as "miRISC."
Dicer processing of the pre-miRNA is thought to be coupled with unwinding of the
duplex. Generally, only one strand is incorporated into the miRISC, selected on the basis
of its thermodynamic instability and weaker base-pairing relative to the other strand.(Krol
et al., 2004)(Khvorova et al., 2003; Schwarz et al., 2003) The position of the stem-loop
may also influence strand choice. (Lin et al., 2005) 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.(Okamura et al., 2008)
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.[55] The human genome encodes eight argonaute proteins divided
by sequence similarities into two families: AGO (with four members present in all
mammalian cells and called E1F2C/hAgo in humans), and PIWI (found in the germ line
and hematopoietic stem cells).[55][56]
Additional RISC components include TRBP [human immunodeficiency virus (HIV)
transactivating response RNA (TAR) binding protein],[57] PACT (protein activator of the
interferon induced protein kinase (PACT), the SMN complex, fragile X mental
retardation protein (FMRP), and Tudor staphylococcal nuclease-domain-containing
protein (Tudor-SN).[58][59]
[edit] Turnover of mature microRNAs
miRNA biogenesis is highly regulated. It is controlled at both transcriptional and posttranscriptional 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.[60]
[edit] 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.[61] Perfect or near perfect base pairing with
the target RNA promotes cleavage of the RNA.[62] This is the primary mode of plant
microRNAs.[63] In animals, microRNAs more often only partially base pair and inhibit
protein translation of the target mRNA[64] (this exists in plants as well but is less
common).[63] MicroRNAs that are partially complementary to the target can also speed up
deadenylation, causing mRNAs to be degraded sooner.[65] For partially complementary
microRNA to recognise their targets, the nucleotides 2–7 of the miRNA ('seed region'),
still have to be perfectly complementary.[66] miRNAs occasionally also causes DNA
methylation of promoter sites and therefore affecting the expression of targeted
genes.[67][68]
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.[69]
[edit] 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),[70] but has also
been demonstrated for endogenous microRNA.[71]
[edit] Experimental detection and manipulation of
miRNA
MicroRNA expression can be quantified by modified RT-PCR followed by QPCR[72], or
profiled against a database describing thousands of known miRNAs using microarray
technology.[73] The activity of an miRNA can be experimentally inhibited using a locked
nucleic acid oligo, a Morpholino oligo[74][75] or a 2'-O-methyl RNA oligo.[76] MicroRNA
maturation can be inhibited at several points by steric-blocking oligos.[77] The miRNA
target site of an mRNA transcript can also be blocked by a steric-blocking oligo.[78][79]
Additionally, a specific miRNA can be silenced by a complementary antagomir.
[edit] miRNA and disease
Just as miRNA is involved in the normal functioning of eukaryotic cells, so has
dysregulation of miRNA been associated with disease. A manually curated, publicly
available database miR2Disease documents known relationships between miRNA
dysregulation and human disease.[80]
[edit] miRNA and cancer
Several miRNAs have been found to have links with some types of cancer.[81][82]
A study of mice altered to produce excess c-Myc — a protein with mutated forms
implicated in several cancers — shows that miRNA has an effect on the development of
cancer. Mice that were engineered to produce a surplus of types of miRNA found in
lymphoma cells developed the disease within 50 days and died two weeks later. In
contrast, mice without the surplus miRNA lived over 100 days.[83] 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.[84]
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.[85]
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.[86]
[edit] 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.[87][88] miRNA expression profiling studies
demonstrate that expression levels of specific miRNAs change in diseased human hearts,
pointing to their involvement in cardiomyopathies.[89][90][91] 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.[88][92][93][94][95][96]
[edit] Other conditions
One study implicates miRNA as a factor in the development of schizophrenia.[97]
[edit] miRNA and non-coding RNAs
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.[98] Since
then, the advent of sophisticated bioinformatics approaches combined with genome tiling
studies examining the transcriptome,[99] systematic sequencing of full length cDNA
libraries,[100] and experimental validation[101] (including the creation of miRNA derived
antisense oligonucleotides called antagomirs) have revealed that many transcripts are for
non protein-coding RNA, including snoRNA and miRNA.[102]
[edit] References
1. ^
1. REDIRECTTemplate:Cite doi/10.1016.2Fj.cell.2009.01.002 edit






^ Bartel, D. P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and
function. Cell 116, 281-297.
^ Homo sapiens miRNAs in the miRBase at Manchester University
^ 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.
^ 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, 92105.
^ 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.
^ Brennecke, J., Stark, A., Russell, R. B., and Cohen, S. M. (2005). Principles of
microRNA-target recognition. PLoS Biol 3, e85.















^ 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.
^ Tanzer, A., and Stadler, P. F. (2004). Molecular evolution of a microRNA
cluster. J Mol Biol 339, 327-335.
^ 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.
^ 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.
^ Grosshans, H., and Slack, F. J. (2002). Micro-RNAs: small is plentiful. J Cell
Biol 156, 17-21.
^ 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.
^ 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, 2536.
^ Cuellar, T. L., and McManus, M. T. (2005). MicroRNAs and endocrine biology.
J Endocrinol 187, 327-332.
^ 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, 226230.
^ Chen, C. Z., Li, L., Lodish, H. F., and Bartel, D. P. (2004). MicroRNAs
modulate hematopoietic lineage differentiation. Science 303, 83-86.
^ 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.
^ 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.
^ 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.
^ Lagos-Quintana, M., Rauhut, R., Meyer, J., Borkhardt, A., and Tuschl, T.
(2003). New microRNAs from mouse and human. Rna 9, 175-179.
^ 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.

^ PMID 19956180 (PubMed)
Citation will be completed automatically in a few minutes. Jump the queue or expand
by hand

^ PMID 19876744 (PubMed)
Citation will be completed automatically in a few minutes. Jump the queue or expand
by hand

^ PMID 19896977 (PubMed)
Citation will be completed automatically in a few minutes. Jump the queue or expand
by hand













^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ a b 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.
^ a b c d e f 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.
^ Lagos-Quintana, M., Rauhut, R., Lendeckel, W., and Tuschl, T. (2001).
Identification of novel genes coding for small expressed RNAs. Science 294, 853858.
^ Lee, R. C., and Ambros, V. (2001). An extensive class of small RNAs in
Caenorhabditis elegans. Science 294, 862-864.
^ 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.
^ a b c d 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.
^ Weber, M. J. (2005). New human and mouse microRNA genes found by
homology search. Febs J 272, 59-73.
^ Kim, Y. K., and Kim, V. N. (2007). Processing of intronic microRNAs. Embo J
26, 775-783.







^ Baskerville, S., and Bartel, D. P. (2005). Microarray profiling of microRNAs
reveals frequent coexpression with neighboring miRNAs and host genes. Rna 11,
241-247.
^ 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.
^ 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.
^ 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.
^ 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.
^ Faller, M.; Guo, F. (2008). "MicroRNA biogenesis: there's more than one way
to skin a cat.". Biochimica et biophysica acta 1779 (11): 663–667.
doi:10.1016/j.bbagrm.2008.08.005. PMID 18778799. edit
^ PMID 16957365 (PubMed)
Citation will be completed automatically in a few minutes. Jump the queue or expand
by hand

^ PMID 17964270 (PubMed)
Citation will be completed automatically in a few minutes. Jump the queue or expand
by hand

^ a b PMID 18684997 (PubMed)
Citation will be completed automatically in a few minutes. Jump the queue or expand
by hand

^ PMID 19255566 (PubMed)
Citation will be completed automatically in a few minutes. Jump the queue or expand
by hand

^ PMID 17628290 (PubMed)
Citation will be completed automatically in a few minutes. Jump the queue or expand
by hand

^ PMID 15145345 (PubMed)
Citation will be completed automatically in a few minutes. Jump the queue or expand
by hand

^ a b c PMID 17381281 (PubMed)
Citation will be completed automatically in a few minutes. Jump the queue or expand
by hand

^ PMID 18268841 (PubMed)
Citation will be completed automatically in a few minutes. Jump the queue or expand
by hand

^ doi:10.1038/nrm2085
This citation will be automatically completed in the next few minutes. You can jump
the queue or expand by hand

^ PMID 12000786 (PubMed)
Citation will be completed automatically in a few minutes. Jump the queue or expand
by hand

^ a b doi:10.1074/jbc.R900012200
This citation will be automatically completed in the next few minutes. You can jump
the queue or expand by hand

^ doi:10.1101/gad.992502
This citation will be automatically completed in the next few minutes. You can jump
the queue or expand by hand

^ PMID 18178619 (PubMed)
Citation will be completed automatically in a few minutes. Jump the queue or expand
by hand

^ doi:10.1016/j.ceb.2004.04.003
This citation will be automatically completed in the next few minutes. You can jump
the queue or expand by hand











^ Mourelatos Z, Dostie J, Paushkin S, et al. (March 2002). "miRNPs: a novel
class of ribonucleoproteins containing numerous microRNAs". Genes Dev. 16 (6):
720–8. doi:10.1101/gad.974702. PMID 11914277.
^ Chatterjee S, Großhans H (September 2009). "Active turnover modulates
mature microRNA activity in Caenorhabditis elegans". Nature 461: 546–459.
doi:10.1038/nature08349.
^ 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. PMID 15345049.
PMC 522872. http://genomebiology.com/2004/5/9/R65.
^ 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.
^ a b Moxon S, Jing R, Szittya G, et al. (October 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.
PMID 18653800.
^ Williams AE (February 2008). "Functional aspects of animal microRNAs". Cell.
Mol. Life Sci. 65 (4): 545–62. doi:10.1007/s00018-007-7355-9. PMID 17965831.
^ Eulalio A, Huntzinger E, Nishihara T, Rehwinkel J, Fauser M, Izaurralde E
(January 2009). "Deadenylation is a widespread effect of miRNA regulation".
RNA 15 (1): 21–32. doi:10.1261/rna.1399509. PMID 19029310.
^ Mazière P, Enright AJ (June 2007). "Prediction of microRNA targets". Drug
Discov. Today 12 (11-12): 452–8. doi:10.1016/j.drudis.2007.04.002.
PMID 17532529.
^ Tan Y, Zhang B, Wu T, et al. (February 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. PMID 19232136.
^ Hawkins PG, Morris KV (March 2008). "RNA and transcriptional modulation
of gene expression". Cell Cycle 7 (5): 602–7. PMID 18256543.
http://www.landesbioscience.com/journals/cc/abstract.php?id=5522.
^ 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.












^ 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. http://www.horizonpress.com/rnareg.
^ 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.
PMID 18227514.
^ Caifu, Chen; Dana A. Ridzon, Adam J. Broomer, Zhaohui Zhou, Danny H. Lee,
Julie T. Nguyen, Maura Barbisin, Nan Lan Xu, Vikram R. Mahuvakar, Mark R.
Andersen, Kai Qin Lao, Kenneth J. Livak and Karl J. Guegler (2005-10-25).
"Real-time quantification of microRNAs by stem–loop RT–PCR". Nucleic Acids
Research 33 (20): e179. doi:10.1093/nar/gni178.
^ Jaclyn, Shingara; KERRI KEIGER, JEFFREY SHELTON, WALAIRAT
LAOSINCHAI-WOLF, PATRICIA POWERS, RICHARD CONRAD, DAVID
BROWN, EMMANUEL LABOURIER (2005-07-25). "An optimized isolation
and labeling platform for accurate microRNA expression profiling". RNA 11 (9):
1461–1470. doi:10.1261/rna.2610405. PMID 16043497.
^ 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. PMID 15585662.
^ Flynt AS, Li N, Thatcher EJ, Solnica-Krezel L, Patton JG (February 2007).
"Zebrafish miR-214 modulates Hedgehog signaling to specify muscle cell fate".
Nat. Genet. 39 (2): 259–63. doi:10.1038/ng1953. PMID 17220889.
^ Meister G, Landthaler M, Dorsett Y, Tuschl T (March 2004). "Sequencespecific inhibition of microRNA- and siRNA-induced RNA silencing". RNA 10
(3): 544–50. doi:10.1261/rna.5235104. PMID 14970398.
^ Kloosterman WP, Lagendijk AK, Ketting RF, Moulton JD, Plasterk RH
(August 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. PMID 17676975.
^ Choi, WY; Giraldez AJ, Schier AF (2007). "Target Protectors Reveal
Dampening and Balancing of Nodal Agonist and Antagonist by miR-430."
(Pubmed). Science. 318 (5848): 271–4. doi:10.1126/science.1147535.
PMID 17761850.
^ Klein, E.; Lioy, T.; Ma, L.; Impey, S.; Mandel, G.; Goodman, H. (Dec 2007).
"Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA".
Nature neuroscience 10 (12): 1513–1514. doi:10.1038/nn2010. ISSN 1097-6256.
PMID 17994015. edit
^ Jiang Q, Wang Y, Hao Y, Juan L, Teng M, Zhang X, Li M, Wang G, Liu Y.
(January 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. PMID 18927107.
^ He L, Thomson JM, Hemann MT, et al. (June 2005). "A microRNA polycistron
as a potential human oncogene". Nature 435 (7043): 828–33.
doi:10.1038/nature03552. PMID 15944707.













^ Mraz M, Pospisilova S, Malinova K, et al. (March 2009). "MicroRNAs in
chronic lymphocytic leukemia pathogenesis and disease subtypes". Leuk
Lymphoma 50 (3): 506–9. doi:10.1080/10428190902763517. PMID 19347736.
^ He L, Thomson JM, Hemann MT, et al. (June 2005). "A microRNA polycistron
as a potential human oncogene". Nature 435 (7043): 828–33.
doi:10.1038/nature03552. PMID 15944707.
^ Cui JW, Li YJ, Sarkar A, Brown J, Tan YH, Premyslova M, Michaud C, Iscove
N, Wang GJ, Ben-David Y. (June 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.
^ O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT (June 2005). "cMyc-regulated microRNAs modulate E2F1 expression". Nature 435 (7043): 839–
43. doi:10.1038/nature03677. PMID 15944709.
^ Lu J, Getz G, Miska EA, et al. (June 2005). "MicroRNA expression profiles
classify human cancers". Nature 435 (7043): 834–8. doi:10.1038/nature03702.
PMID 15944708.
^ Chen JF, Murchison EP, Tang R, et al. (February 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.
PMID 18256189.
^ a b Zhao Y, Ransom JF, Li A, et al. (April 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.
^ Thum T, Galuppo P, Wolf C, et al. (July 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.
^ van Rooij E, Sutherland LB, Liu N, et al. (November 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. PMID 17108080.
^ Tatsuguchi M, Seok HY, Callis TE, et al. (June 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.
PMID 17498736.
^ Zhao Y, Samal E, Srivastava D (July 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.
^ Xiao J, Luo X, Lin H, et al. (April 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.
http://www.jbc.org/cgi/pmidlookup?view=long&pmid=17344217.
^ Yang B, Lin H, Xiao J, et al. (April 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.








^ Carè A, Catalucci D, Felicetti F, et al. (May 2007). "MicroRNA-133 controls
cardiac hypertrophy". Nat. Med. 13 (5): 613–8. doi:10.1038/nm1582.
PMID 17468766.
^ van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN (April
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.
http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=17379774.
^ 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
^ Pheasant, M., and Mattick, J. S. (2007). Raising the estimate of functional
human sequences. Genome Res 17, 1245-1253.
^ 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.
^ 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.
^ 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, 4754.
^ Huttenhofer, A., Schattner, P., and Polacek, N. (2005). Non-coding RNAs: hope
or hype? Trends Genet 21, 289-297.
[edit] Further reading




This paper discusses the role of microRNAs in viral oncogenesis: Scaria V;
Jadhav, Vaibhav (2007). "microRNAs in viral oncogenesis.". Retrovirology 4 (82):
68. doi:10.1186/1742-4690-4-82.
This paper discusses the role of microRNAs in Host-virus interactions: Scaria V;
Hariharan, M; Maiti, S; Pillai, B; Brahmachari, SK (2006). "Host-Virus
Interaction: A new role for microRNAs.". Retrovirology 3 (1): 68.
doi:10.1186/1742-4690-3-68. PMID 17032463.
This paper defines miRNA and proposes guidelines to follow in classifying RNA
genes as miRNA: Ambros V, Bartel B, Bartel DP, Burge CB, Carrington JC, Chen
X, Dreyfuss G, Eddy SR, Griffiths-Jones S, Marshall M, Matzke M, Ruvkun G,
Tuschl T (2003). "A uniform system for microRNA annotation". RNA 9 (3): 277–
279. doi:10.1261/rna.2183803. PMID 12592000.
This paper discusses the processes that miRNA and siRNAs are involved in, in the
context of 2 articles in the same issue of the journal Science: Baulcombe D
(2002). "DNA events. An RNA microcosm.". Science 297 (5589): 2002–2003.
doi:10.1126/science.1077906. PMID 12242426.

[
This paper describes the discovery of lin-4, the first miRNA to be discovered: Lee
RC, Feinbaum RL, Ambros V (1993). "The C. elegans heterochronic gene lin-4
encodes small RNAs with antisense complementarity to lin-14". Cell 75 (5): 843–
854. doi:10.1016/0092-8674(93)90529-Y. PMID 8252621.