microRNA
MicroRNA (miRNA) are small, single-stranded,
- Cleavage of the mRNA strand into two pieces,
- Destabilization of the mRNA by shortening its poly(A) tail, or
- Reducing translation of the mRNA into proteins.
In cells of humans and other animals, miRNAs primarily act by destabilizing the mRNA.[6][7]
miRNAs resemble the
miRNAs are abundant in many mammalian cell types[11][12] miRNAs appear to target about 60% of the genes of humans and other mammals.[13][14] Many miRNAs are evolutionarily conserved, which implies that they have important biological functions.[15][1] For example, 90 families of miRNAs have been conserved since at least the common ancestor of mammals and fish, and most of these conserved miRNAs have important functions, as shown by studies in which genes for one or more members of a family have been knocked out in mice.[1]
History
The first miRNA was discovered in the early 1990s.[16] However, miRNAs were not recognized as a distinct class of biological regulators until the early 2000s.[17][18][19][20][21] miRNA research revealed different sets of miRNAs expressed in different cell types and tissues[12][22] and multiple roles for miRNAs in plant and animal development and in many other biological processes.[23][24][25][26][27][28][29] Aberrant miRNA expression are implicated in disease states. MiRNA-based therapies are under investigation.[30][31][32][33]
The first miRNA was discovered in 1993 by a group led by
In 2000, a second small RNA was characterized: let-7 RNA, which represses lin-41 to promote a later developmental transition in C. elegans.[17] The let-7 RNA was found to be conserved in many species, leading to the suggestion that let-7 RNA and additional "small temporal RNAs" might regulate the timing of development in diverse animals, including humans.[18]
A year later, the lin-4 and let-7 RNAs were found to be part of a large class of small RNAs present in C. elegans, Drosophila and human cells.[19][20][21] The many RNAs of this class resembled the lin-4 and let-7 RNAs, except their expression patterns were usually inconsistent with a role in regulating the timing of development. This suggested that most might function in other types of regulatory pathways. At this point, researchers started using the term "microRNA" to refer to this class of small regulatory RNAs.[19][20][21]
The first human disease associated with deregulation of miRNAs was
Nomenclature
Under a standard nomenclature system, names are assigned to experimentally confirmed miRNAs before publication.[36][37] The prefix "miR" is followed by a dash and a number, the latter often indicating order of naming. For example, miR-124 was named and likely discovered prior to miR-456. A capitalized "miR-" refers to the mature form of the miRNA, while the uncapitalized "mir-" refers to the pre-miRNA and the pri-miRNA.[38] The genes encoding miRNAs are also named using the same three-letter prefix according to the conventions of the organism gene nomenclature. For examples, the official miRNAs gene names in some organisms are "mir-1 in C. elegans and Drosophila, Mir1 in Rattus norvegicus and MIR25 in human.
miRNAs with nearly identical sequences except for one or two nucleotides are annotated with an additional lower case letter. For example, miR-124a is closely related to miR-124b. For example:
- hsa-miR-181a: aacauucaACgcugucggugAgu
- hsa-miR-181b: aacauucaUUgcugucggugGgu
Pre-miRNAs, pri-miRNAs and genes that lead to 100% identical mature miRNAs but that are located at different places in the genome are indicated with an additional dash-number suffix. For example, the pre-miRNAs hsa-mir-194-1 and hsa-mir-194-2 lead to an identical mature miRNA (hsa-miR-194) but are from genes located in different genome regions.
Species of origin is designated with a three-letter prefix, e.g., hsa-miR-124 is a human (Homo sapiens) miRNA and oar-miR-124 is a sheep (Ovis aries) miRNA. Other common prefixes include "v" for viral (miRNA encoded by a viral genome) and "d" for Drosophila miRNA (a fruit fly commonly studied in genetic research).
When two mature microRNAs originate from opposite arms of the same pre-miRNA and are found in roughly similar amounts, they are denoted with a -3p or -5p suffix. (In the past, this distinction was also made with "s" (
Targets
Plant miRNAs usually have near-perfect pairing with their mRNA targets, which induces gene repression through cleavage of the target transcripts.[23][39] In contrast, animal miRNAs are able to recognize their target mRNAs by using as few as 6–8 nucleotides (the seed region) at the 5' end of the miRNA,[13][40][41] which is not enough pairing to induce cleavage of the target mRNAs.[4] Combinatorial regulation is a feature of miRNA regulation in animals.[4][42] A given miRNA may have hundreds of different mRNA targets, and a given target might be regulated by multiple miRNAs.[14][43]
Estimates of the average number of unique messenger RNAs that are targets for repression by a typical miRNA vary, depending on the estimation method,[44] but multiple approaches show that mammalian miRNAs can have many unique targets. For example, an analysis of the miRNAs highly conserved in vertebrates shows that each has, on average, roughly 400 conserved targets.[14] Likewise, experiments show that a single miRNA species can reduce the stability of hundreds of unique messenger RNAs.[45] Other experiments show that a single miRNA species may repress the production of hundreds of proteins, but that this repression often is relatively mild (much less than 2-fold).[46][47]
Biogenesis
As many as 40% of miRNA genes may lie in the introns or even exons of other genes.[48] These are usually, though not exclusively, found in a sense orientation,[49][50] and thus usually are regulated together with their host genes.[48][51][52]
The DNA template is not the final word on mature miRNA production: 6% of human miRNAs show RNA editing (
Transcription
miRNA genes are usually transcribed by
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 (dsRNA) structure of the hairpins in a pri-miRNA is recognized by a nuclear protein known as
Pre-miRNAs that are
As many as 16% of pre-miRNAs may be altered through nuclear RNA editing.[66][67][68] 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).[66]
Nuclear export
Pre-miRNA hairpins are exported from the nucleus in a process involving the nucleocytoplasmic shuttler
Cytoplasmic processing
In the cytoplasm, the pre-miRNA hairpin is cleaved by the RNase III enzyme Dicer.[70] This endoribonuclease interacts with 5' and 3' ends of the hairpin[71] and cuts away the loop joining the 3' and 5' arms, yielding an imperfect miRNA:miRNA* duplex about 22 nucleotides in length.[70] Overall hairpin length and loop size influence the efficiency of Dicer processing. The imperfect nature of the miRNA:miRNA* pairing also affects cleavage.[70][72] Some of the G-rich pre-miRNAs can potentially adopt the G-quadruplex structure as an alternative to the canonical stem-loop structure. For example, human pre-miRNA 92b adopts a G-quadruplex structure which is resistant to the Dicer mediated cleavage in the cytoplasm.[73] 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.
While the majority of miRNAs are located within the cell, some miRNAs, commonly known as circulating miRNAs or extracellular miRNAs, have also been found in extracellular environment, including various biological fluids and cell culture media.[74][75]
Biogenesis in plants
miRNA biogenesis in plants differs from animal biogenesis mainly in the steps of nuclear processing and export. Instead of being cleaved by two different enzymes, once inside and once outside the nucleus, both cleavages of the plant miRNA are performed by a Dicer homolog, called
RNA-induced silencing complex
The mature miRNA is part of an active RNA-induced silencing complex (RISC) containing Dicer and many associated proteins.[77] RISC is also known as a microRNA ribonucleoprotein complex (miRNP);[78] A RISC with incorporated miRNA is sometimes referred to as a "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 on the 5' end relative to the other strand.[79][80][81] The position of the stem-loop may also influence strand choice.[82] 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.[83]
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.[84] The human genome encodes eight argonaute proteins divided by sequence similarities into two families: AGO (with four members present in all mammalian cells and called E1F2C/hAgo in humans), and PIWI (found in the germline and hematopoietic stem cells).[78][84]
Additional RISC components include TRBP [human immunodeficiency virus (HIV) transactivating response RNA (TAR) binding protein],[85] PACT (protein activator of the interferon-induced protein kinase), the SMN complex, fragile X mental retardation protein (FMRP), Tudor staphylococcal nuclease-domain-containing protein (Tudor-SN), the putative DNA helicase MOV10, and the RNA recognition motif containing protein TNRC6B.[69][86][87]
Mode of silencing and regulatory loops
Gene silencing may occur either via mRNA degradation or preventing mRNA from being translated. For example, miR16 contains a sequence complementary to the AU-rich element found in the 3'UTR of many unstable mRNAs, such as
Turnover
Turnover of mature miRNA is needed for rapid changes in miRNA expression profiles. During miRNA maturation in the cytoplasm, uptake by the Argonaute protein is thought to stabilize the guide strand, while the opposite (* or "passenger") strand is preferentially destroyed. In what has been called a "Use it or lose it" strategy, Argonaute may preferentially retain miRNAs with many targets over miRNAs with few or no targets, leading to degradation of the non-targeting molecules.[89]
Decay of mature miRNAs in
Several miRNA modifications affect miRNA stability. As indicated by work in the model organism Arabidopsis thaliana (thale cress), mature plant miRNAs appear to be stabilized by the addition of methyl moieties at the 3' end. The 2'-O-conjugated methyl groups block the addition of uracil (U) residues by uridyltransferase enzymes, a modification that may be associated with miRNA degradation. However, uridylation may also protect some miRNAs; the consequences of this modification are incompletely understood. Uridylation of some animal miRNAs has been reported. Both plant and animal miRNAs may be altered by addition of adenine (A) residues to the 3' end of the miRNA. An extra A added to the end of mammalian miR-122, a liver-enriched miRNA important in hepatitis C, stabilizes the molecule and plant miRNAs ending with an adenine residue have slower decay rates.[89]
Cellular functions
The function of miRNAs appears to be in gene regulation. For that purpose, a miRNA is
For partially complementary microRNAs to recognise their targets, nucleotides 2–7 of the miRNA (its 'seed region'
miRNAs occasionally also cause
Nine mechanisms of miRNA action are described and assembled in a unified mathematical model:[91]
- Cap-40S initiation inhibition;
- 60S Ribosomal unit joining inhibition;
- Elongation inhibition;
- Ribosome drop-off (premature termination);
- Co-translational nascent protein degradation;
- Sequestration in P-bodies;
- mRNA decay (destabilisation);
- mRNA cleavage;
- Transcriptional inhibition through microRNA-mediated chromatin reorganization followed by gene silencing.
It is often impossible to discern these mechanisms using experimental data about stationary reaction rates. Nevertheless, they are differentiated in dynamics and have different kinetic signatures.[91]
Unlike plant microRNAs, the animal microRNAs target diverse genes.[40] However, genes involved in functions common to all cells, such as gene expression, have relatively fewer microRNA target sites and seem to be under selection to avoid targeting by microRNAs.[102] There is a strong correlation between ITPR gene regulations and mir-92 and mir-19.[103]
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),[104] but has also been demonstrated for endogenous microRNA.[105]
Interactions between microRNAs and complementary sequences on genes and even
miRNAs are also found as extracellular circulating miRNAs.[107] Circulating miRNAs are released into body fluids including blood and cerebrospinal fluid and have the potential to be available as biomarkers in a number of diseases.[107][108]Some researches show that mRNA cargo of exosomes may have a role in implantation, they can savage an adhesion between trophoblast and endometrium or support the adhesion by down regulating or up regulating expression of genes involved in adhesion/invasion.[109]
Moreover, miRNA as miR-183/96/182 seems to play a key role in circadian rhythm.[110]
Evolution
miRNAs are well conserved in both plants and animals, and are thought to be a vital and evolutionarily ancient component of gene regulation.[111][112][113][114][115] While core components of the microRNA pathway are conserved between plants and animals, miRNA repertoires in the two kingdoms appear to have emerged independently with different primary modes of action.[116][117]
microRNAs are useful phylogenetic markers because of their apparently low rate of evolution.[118] microRNAs' origin as a regulatory mechanism developed from previous RNAi machinery that was initially used as a defense against exogenous genetic material such as viruses.[119] Their origin may have permitted the development of morphological innovation, and by making gene expression more specific and 'fine-tunable', permitted the genesis of complex organs[120] and perhaps, ultimately, complex life.[115] Rapid bursts of morphological innovation are generally associated with a high rate of microRNA accumulation.[118][120]
New microRNAs are created in multiple ways. Novel microRNAs can originate from the random formation of hairpins in "non-coding" sections of DNA (i.e. introns or intergene regions), but also by the duplication and modification of existing microRNAs.[121] microRNAs can also form from inverted duplications of protein-coding sequences, which allows for the creation of a foldback hairpin structure.[122] The rate of evolution (i.e. nucleotide substitution) in recently originated microRNAs is comparable to that elsewhere in the non-coding DNA, implying evolution by neutral drift; however, older microRNAs have a much lower rate of change (often less than one substitution per hundred million years),[115] suggesting that once a microRNA gains a function, it undergoes purifying selection.[121] Individual regions within an miRNA gene face different evolutionary pressures, where regions that are vital for processing and function have higher levels of conservation.[123] At this point, a microRNA is rarely lost from an animal's genome,[115] although newer microRNAs (thus presumably non-functional) are frequently lost.[121] In Arabidopsis thaliana, the net flux of miRNA genes has been predicted to be between 1.2 and 3.3 genes per million years.[124] This makes them a valuable phylogenetic marker, and they are being looked upon as a possible solution to outstanding phylogenetic problems such as the relationships of arthropods.[125] On the other hand, in multiple cases microRNAs correlate poorly with phylogeny, and it is possible that their phylogenetic concordance largely reflects a limited sampling of microRNAs.[126]
microRNAs feature in the genomes of most eukaryotic organisms, from the brown algae[127] to the animals. However, the difference in how these microRNAs function and the way they are processed suggests that microRNAs arose independently in plants and animals.[128]
Focusing on the animals, the genome of
Across all species, in excess of 5000 different miRNAs had been identified by March 2010.[131] Whilst short RNA sequences (50 – hundreds of base pairs) of a broadly comparable function occur in bacteria, bacteria lack true microRNAs.[132]
Experimental detection and manipulation
While researchers focused on miRNA expression in physiological and pathological processes, various technical variables related to microRNA isolation emerged. The stability of stored miRNA samples has been questioned.[75] microRNAs degrade much more easily than mRNAs, partly due to their length, but also because of ubiquitously present RNases. This makes it necessary to cool samples on ice and use RNase-free equipment.[133]
microRNA expression can be quantified in a two-step
High-throughput quantification of miRNAs is error prone, for the larger variance (compared to
Human and animal diseases
Just as miRNA is involved in the normal functioning of eukaryotic cells, so has dysregulation of miRNA been associated with disease. A manually curated, publicly available database, miR2Disease, documents known relationships between miRNA dysregulation and human disease.[151]
Inherited diseases
A mutation in the seed region of miR-96 causes hereditary progressive hearing loss.[152]
A mutation in the seed region of miR-184 causes hereditary keratoconus with anterior polar cataract.[153]
Deletion of the miR-17~92 cluster causes skeletal and growth defects.[154]
Cancer
The first human disease known to be associated with miRNA deregulation was chronic lymphocytic leukemia.[155] Many other miRNAs also have links with cancer and accordingly are sometimes referred to as "oncomirs".[156] In malignant B cells miRNAs participate in pathways fundamental to B cell development like B-cell receptor (BCR) signalling, B-cell migration/adhesion, cell-cell interactions in immune niches and the production and class-switching of immunoglobulins. MiRNAs influence B cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and memory B cells.[157]
Another role for miRNA in cancers is to use their expression level for prognosis. In
Furthermore, specific miRNAs may be associated with certain histological subtypes of colorectal cancer. For instance, expression levels of miR-205 and miR-373 have been shown to be increased in mucinous colorectal cancers and mucin-producing Ulcerative Colitis-associated colon cancers, but not in sporadic colonic adenocarcinoma that lack mucinous components.[160] In-vitro studies suggested that miR-205 and miR-373 may functionally induce different features of mucinous-associated neoplastic progression in intestinal epithelial cells.[160]
Hepatocellular carcinoma cell proliferation may arise from miR-21 interaction with MAP2K3, a tumor repressor gene.
MicroRNAs have the potential to be used as tools or targets for treatment of different cancers.[163] The specific microRNA, miR-506 has been found to work as a tumor antagonist in several studies. A significant number of cervical cancer samples were found to have downregulated expression of miR-506. Additionally, miR-506 works to promote apoptosis of cervical cancer cells, through its direct target hedgehog pathway transcription factor, Gli3.[164][165]
DNA repair and cancer
Many miRNAs can directly target and inhibit cell cycle genes to control cell proliferation. A new strategy for tumor treatment is to inhibit tumor cell proliferation by repairing the defective miRNA pathway in tumors.[166] Cancer is caused by the accumulation of mutations from either DNA damage or uncorrected errors in DNA replication.[167] Defects in DNA repair cause the accumulation of mutations, which can lead to cancer.[168] Several genes involved in DNA repair are regulated by microRNAs.[169]
In 29–66%
Single Nucleotide polymorphisms (SNPs) can alter the binding of miRNAs on 3'UTRs for example the case of hsa-mir181a and hsa-mir181b on the CDON tumor suppressor gene.[179]
Heart disease
The global role of miRNA function in the heart has been addressed by conditionally inhibiting miRNA maturation in the murine heart. This revealed that miRNAs play an essential role during its development.[180][181] miRNA expression profiling studies demonstrate that expression levels of specific miRNAs change in diseased human hearts, pointing to their involvement in cardiomyopathies.[182][183][184] Furthermore, animal studies on specific miRNAs identified distinct roles for miRNAs both during heart development and under pathological conditions, including the regulation of key factors important for cardiogenesis, the hypertrophic growth response and cardiac conductance.[181][185][186][187][188][189] Another role for miRNA in cardiovascular diseases is to use their expression levels for diagnosis, prognosis or risk stratification.[190] miRNA's in animal models have also been linked to cholesterol metabolism and regulation.
miRNA-712
Origin
Pre-mRNA sequence of miR-712 is generated from the murine ribosomal RN45s gene at the internal transcribed spacer region 2 (ITS2).[192] XRN1 is an exonuclease that degrades the ITS2 region during processing of RN45s.[192] Reduction of XRN1 under d-flow conditions therefore leads to the accumulation of miR-712.[192]
Mechanism
MiR-712 targets tissue inhibitor of metalloproteinases 3 (TIMP3).[192] TIMPs normally regulate activity of matrix metalloproteinases (MMPs) which degrade the extracellular matrix (ECM). Arterial ECM is mainly composed of collagen and elastin fibers, providing the structural support and recoil properties of arteries.[193] These fibers play a critical role in regulation of vascular inflammation and permeability, which are important in the development of atherosclerosis.[194] Expressed by endothelial cells, TIMP3 is the only ECM-bound TIMP.[193] A decrease in TIMP3 expression results in an increase of ECM degradation in the presence of d-flow. Consistent with these findings, inhibition of pre-miR712 increases expression of TIMP3 in cells, even when exposed to turbulent flow.[192]
TIMP3 also decreases the expression of TNFα (a pro-inflammatory regulator) during turbulent flow.[192] Activity of TNFα in turbulent flow was measured by the expression of TNFα-converting enzyme (TACE) in blood. TNFα decreased if miR-712 was inhibited or TIMP3 overexpressed,[192] suggesting that miR-712 and TIMP3 regulate TACE activity in turbulent flow conditions.
Anti-miR-712 effectively suppresses d-flow-induced miR-712 expression and increases TIMP3 expression.[192] Anti-miR-712 also inhibits vascular hyperpermeability, thereby significantly reducing atherosclerosis lesion development and immune cell infiltration.[192]
Human homolog microRNA-205
The human homolog of miR-712 was found on the RN45s homolog gene, which maintains similar miRNAs to mice.[192] MiR-205 of humans share similar sequences with miR-712 of mice and is conserved across most vertebrates.[192] MiR-205 and miR-712 also share more than 50% of the cell signaling targets, including TIMP3.[192]
When tested, d-flow decreased the expression of XRN1 in humans as it did in mice endothelial cells, indicating a potentially common role of XRN1 in humans.[192]
Kidney disease
Targeted deletion of Dicer in the
Nervous system
MiRNAs are crucial for the healthy development and function of the nervous system.[196] Previous studies demonstrate that miRNAs can regulate neuronal differentiation and maturation at various stages.[197] MiRNAs also play important roles in synaptic development[198] (such as dendritogenesis or spine morphogenesis) and synaptic plasticity[199] (contributing to learning and memory). Elimination of miRNA formation in mice by experimental silencing of Dicer has led to pathological outcomes, such as reduced neuronal size, motor abnormalities (when silenced in striatal neurons[200]), and neurodegeneration (when silenced in forebrain neurons[201]). Altered miRNA expression has been found in neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, and Huntington's disease[202]) as well as many psychiatric disorders (including epilepsy,[203] schizophrenia, major depression, bipolar disorder, and anxiety disorders[204][205][206]).
Stroke
According to the Center for Disease Control and Prevention, Stroke is one of the leading causes of death and long-term disability in America. 87% of the cases are
Alcoholism
The vital role of miRNAs in gene expression is significant to
miRNAs can be either upregulated or downregulated in response to chronic alcohol use.
Obesity
miRNAs play crucial roles in the regulation of
This paves the way for possible genetic obesity treatments.Another class of miRNAs that regulate
Hemostasis
miRNAs also play crucial roles in the regulation of complex enzymatic cascades including the hemostatic blood coagulation system.[222] Large scale studies of functional miRNA targeting have recently uncovered rationale therapeutic targets in the hemostatic system.[223][224] They have been directly linked to Calcium homeostasis in the endoplasmic reticulum, which is critical in cell differentiation in early development.[225]
Plants
miRNAs are considered to be key regulators of many developmental, homeostatic, and immune processes in plants.[226] Their roles in plant development include shoot apical meristem development, leaf growth, flower formation, seed production, or root expansion.[227][228][229][230] In addition, they play a complex role in responses to various abiotic stresses comprising heat stress, low-temperature stress, drought stress, light stress, or gamma radiation exposure.[226]
Viruses
Viral microRNAs play an important role in the regulation of gene expression of viral and/or host genes to benefit the virus. Hence, miRNAs play a key role in host–virus interactions and pathogenesis of viral diseases.
Target prediction
miRNAs can bind to target messenger RNA (mRNA) transcripts of protein-coding genes and negatively control their translation or cause mRNA degradation. It is of key importance to identify the miRNA targets accurately.[234] A comparison of the predictive performance of eighteen in silico algorithms is available.[235] Large scale studies of functional miRNA targeting suggest that many functional miRNAs can be missed by target prediction algorithms.[223]
See also
- Anti-miRNA oligonucleotides
- Gene expression
- List of miRNA gene prediction tools
- List of miRNA target prediction tools
- MicroDNA
- MicroRNA Biosensors
- MiRNEST
- MIR222
- miR-324-5p
- RNA interference
- Small interfering RNA
- Small nucleolar RNA-derived microRNA
- C19MC miRNA cluster
References
- ^ PMID 29570994.
- ^ PMID 14744438.
- PMID 25380780.
- ^ PMID 19167326.
- S2CID 24892348.
- S2CID 24892348.
- PMID 20703300.
- Manchester University
- PMID 30820533.
- PMID 31598695.
- PMID 12672692.
- ^ PMID 12007417.
- ^ PMID 15652477.
- ^ PMID 18955434.
- PMID 26473382.
- ^ PMID 8252621.
- ^ S2CID 4384503.
- ^ S2CID 4401732.
- ^ S2CID 18101169.
- ^ S2CID 43262684.
- ^ S2CID 33480585.
- S2CID 38939571.
- ^ PMID 16669754.
- PMID 12679032.
- PMID 16423811.
- S2CID 4415988.
- S2CID 7044929.
- PMID 17521938.
- PMID 16040801.
- PMID 19956180.
- PMID 19876744.
- PMID 19896977.
- PMID 24627783.
- PMID 8252622.
- PMID 26658994.
- PMID 12592000.
- PMID 16381832.
- PMID 21296742.
- PMID 31345162.
- ^ PMID 14697198.
- PMID 21441577.
- S2CID 23496396.
- S2CID 22672750.
- PMID 21652644.
- ^ S2CID 4430576.
- S2CID 4429008.
- PMID 18668037.
- ^ PMID 15364901.
- ^ PMID 15525708.
- S2CID 32923462.
- PMID 17255951.
- PMID 15701730.
- ^ PMID 15372072.
- PMID 17352530.
- PMID 18778799.
- S2CID 4421030.
- PMID 16957365.
- PMID 15574589.
- PMID 16751099.
- PMID 25310978.
- PMID 23415231.
- S2CID 28899778.
- PMID 17589500.
- PMID 17589500.
- PMID 17964270.
- ^ PMID 18684997.
- S2CID 205286318.
- PMID 17628290.
- ^ PMID 15145345.
- ^ PMID 17381281.
- PMID 21753850.
- PMID 18268841.
- PMID 25641166.
- .
- ^ PMID 24508494.
- PMID 20808519.
- S2CID 8966239.
- ^ PMID 12000786.
- PMID 15292246.
- PMID 14567918.
- PMID 14567917.
- PMID 16005165.
- PMID 18769156.
- ^ PMID 19342379.
- PMID 18178619.
- PMID 11914277.
- PMID 16289642.
- PMID 15766526.
- ^ PMID 20051982.
- S2CID 4414841.
- ^ PMID 22850425.
- PMID 15345049.
- PMID 17150553.
- ^ PMID 18653800.
- PMID 17532529.
- S2CID 5708394.
- PMID 19029310.
- PMID 22422859.
- PMID 22499947.
- PMID 19232136.
- PMID 18256543.
- PMID 16337999.
- S2CID 5270062.
- ISBN 978-1-904455-25-7.
- PMID 18227514.
- PMID 21802130.
- ^ PMID 27264337.
- PMID 31816349.
- PMID 26629549.
- S2CID 230713808.
- "MicroRNAs Play Key Role in Regulation of Circadian Rhythms". Science News. 6 January 2021.
- PMID 15849273.
- PMID 15136036.
- S2CID 174231.
- PMID 17465887.
- ^ S2CID 15364875.
- PMID 18715673.
- PMID 21554756.
- ^ S2CID 14924603.
- S2CID 12025420.
- ^ PMID 18287013.
- ^ PMID 20624724.
- S2CID 11997028.
- PMID 18296705.
- PMID 20407027.
- S2CID 20548122.
- PMID 26319627.
- PMID 20520714.
- PMID 21317375.
- PMID 24337300.
- PMID 23256903.
- ^ Dimond PF (15 March 2010). "miRNAs' Therapeutic Potential". Genetic Engineering & Biotechnology News. 30 (6): 1. Archived from the original on 19 July 2010. Retrieved 10 July 2010.
- PMID 16717284.
- S2CID 2441105.
- PMID 16314309.
- PMID 16043497.
- PMID 21171994.
- PMID 15585662.
- PMID 17220889.
- PMID 14970398.
- PMID 17676975.
- PMID 24068553.
- S2CID 30461594.
- PMID 16670427.
- PMID 23213449.
- PMID 16752924.
- PMID 19689821.
- PMID 17612493.
- PMID 17991681.
- PMID 19420067.
- PMID 22723856.
- PMID 18927107.
- S2CID 11113852.
- PMID 21996275.
- PMID 21892160.
- PMID 15284443.
- S2CID 255034585.
- PMID 36010971.
- S2CID 9746594.
- PMID 21573504.
- ^ PMID 27271572.
- ^ MicroRNA-21 promotes hepatocellular carcinoma HepG2 cell proliferation through repression of mitogen-activated protein kinase-kinase 3. Guangxian Xu et al., 2013
- PMID 24222179.
- S2CID 3766576.
- PMID 24604117.
- S2CID 20603801.
- S2CID 249070106. Retrieved 15 September 2022.
- PMID 10688858.
- ISBN 978-1-4641-8339-3.
- PMID 21183529.
- PMID 20420945.
- PMID 15887099.
- PMID 20351277.
- ^ PMID 22570426.
- PMID 20150365.
- S2CID 28903539.
- PMID 15150086.
- PMID 14627817.
- PMID 22494821.
- PMID 25313246.
- PMID 18256189.
- ^ PMID 17397913.
- PMID 17606841.
- PMID 17108080.
- PMID 17498736.
- S2CID 4340449.
- PMID 17344217.
- S2CID 1935811.
- S2CID 10097893.
- S2CID 1927839.
- PMID 28674420.
- PMID 19110086.
- ^ PMID 24346612.
- ^ PMID 23144462.
- S2CID 407449.
- ^ PMID 26438731.
- PMID 27240359.
- PMID 22661924.
- S2CID 3507952.
- PMID 36656826.
- PMID 18385371.
- PMID 20660113.
- PMID 35327979.
- PMID 27839653.
- (PDF) from the original on 23 May 2022.
- PMID 19568434.
- PMID 19721432.
- ^ "Stroke Facts". Centers for Disease Control and Prevention. 15 March 2019. Retrieved 5 December 2019.
- PMID 20841499.
- PMID 23170800.
- ^ PMID 21651580.
- PMID 22614244.
- PMID 24358208.
- PMID 24672003.
- PMID 23951048.
- ^ PMID 23873704.
- S2CID 30646787.
- PMID 21756067.
- PMID 16431920.
- S2CID 3614126.
- PMID 21962509.
- PMID 22160727.
- PMID 25400249.
- ^ PMID 30207063.
- PMID 32898547.
- S2CID 6402014.
- ^ PMID 36499082.
- PMID 22838835.
- S2CID 233685660.
- PMID 32192095.
- PMID 21504877.
- PMID 25380780.
- ^ Kumar M. "VIRmiRNA". Resource for experimental viral miRNA and their targets. Bioinformatics center, CSIR-IMTECH.
- PMID 22114334.
- PMID 23591837.
- PMID 26267216.
Further reading
- miRNA definition and classification: Ambros V, Bartel B, Bartel DP, Burge CB, Carrington JC, Chen X, et al. (March 2003). "A uniform system for microRNA annotation". RNA. 9 (3): 277–9. PMID 12592000.
- S2CID 82531727.
- Discovery of lin-4, the first miRNA to be discovered: Lee RC, Feinbaum RL, Ambros V (December 1993). "The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14". Cell. 75 (5): 843–54. PMID 8252621.
External links
- The miRBase database
- miRTarBase, the experimentally validated microRNA-target interactions database.
- semirna, Web application to search for microRNAs in a plant genome.
- ONCO.IO: Integrative resource for microRNA and transcription factors analysis in cancer.
- MirOB Archived 4 March 2014 at the Wayback Machine: MicroRNA targets database and data analysis and dataviz tool.
- ChIPBase database: An open access database for decoding the transcription factorsthat were involved in or affected the transcription of microRNAs from ChIP-seq data.
- An animated video of the microRNA biogenesis process.
- miRNA modulation reagents to enable up-regulation or suppression of endogenous mature microRNA function