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1.  Features of Mammalian microRNA Promoters Emerge from Polymerase II Chromatin Immunoprecipitation Data 
PLoS ONE  2009;4(4):e5279.
Background
MicroRNAs (miRNAs) are short, non-coding RNA regulators of protein coding genes. miRNAs play a very important role in diverse biological processes and various diseases. Many algorithms are able to predict miRNA genes and their targets, but their transcription regulation is still under investigation. It is generally believed that intragenic miRNAs (located in introns or exons of protein coding genes) are co-transcribed with their host genes and most intergenic miRNAs transcribed from their own RNA polymerase II (Pol II) promoter. However, the length of the primary transcripts and promoter organization is currently unknown.
Methodology
We performed Pol II chromatin immunoprecipitation (ChIP)-chip using a custom array surrounding regions of known miRNA genes. To identify the true core transcription start sites of the miRNA genes we developed a new tool (CPPP). We showed that miRNA genes can be transcribed from promoters located several kilobases away and that their promoters share the same general features as those of protein coding genes. Finally, we found evidence that as many as 26% of the intragenic miRNAs may be transcribed from their own unique promoters.
Conclusion
miRNA promoters have similar features to those of protein coding genes, but miRNA transcript organization is more complex.
doi:10.1371/journal.pone.0005279
PMCID: PMC2668758  PMID: 19390574
2.  Drosha Promotes Splicing of a Pre-microRNA-like Alternative Exon 
PLoS Genetics  2014;10(5):e1004312.
The ribonuclease III enzyme Drosha has a central role in the biogenesis of microRNA (miRNA) by binding and cleaving hairpin structures in primary RNA transcripts into precursor miRNAs (pre-miRNAs). Many miRNA genes are located within protein-coding host genes and cleaved by Drosha in a manner that is coincident with splicing of introns by the spliceosome. The close proximity of splicing and pre-miRNA biogenesis suggests a potential for co-regulation of miRNA and host gene expression, though this relationship is not completely understood. Here, we describe a cleavage-independent role for Drosha in the splicing of an exon that has a predicted hairpin structure resembling a Drosha substrate. We find that Drosha can cleave the alternatively spliced exon 5 of the eIF4H gene into a pre-miRNA both in vitro and in cells. However, the primary role of Drosha in eIF4H gene expression is to promote the splicing of exon 5. Drosha binds to the exon and enhances splicing in a manner that depends on RNA structure but not on cleavage by Drosha. We conclude that Drosha can function like a splicing enhancer and promote exon inclusion. Our results reveal a new mechanism of alternative splicing regulation involving a cleavage-independent role for Drosha in splicing.
Author Summary
MicroRNAs (miRNAs) are short non-coding RNAs that function in gene silencing and are produced by cleavage from a larger primary RNA transcript through a reaction that is carried out by the Microprocessor. Primary miRNA transcripts are often located within the introns of genes. Thus, both the Microprocessor and the spliceosome, which is responsible for pre-mRNA splicing, interact with the same sequences, though little is known about how these two processes influence each other. In this study, we discovered that the alternatively spliced eIF4H exon 5 is predicted to form an RNA hairpin that resembles a Microprocessor substrate. We found that the Microprocessor can bind and cleave exon 5, which precludes inclusion of the exon in the mRNA. However, we find that Drosha, a component of the Microprocessor, primarily functions to enhance exon 5 splicing both in vitro and in cells, rather than to cleave the RNA. Our results suggest that the Microprocessor has a role in splicing that is distinct from its role in miRNA biogenesis. This Microprocessor activity represents a new function for the complex that may be an important mechanism for regulating alternative splicing.
doi:10.1371/journal.pgen.1004312
PMCID: PMC4006729  PMID: 24786770
3.  miRNA-target prediction based on transcriptional regulation 
BMC Genomics  2013;14(Suppl 2):S3.
Background
microRNAs (miRNAs) are tiny endogenous RNAs that have been discovered in animals and plants, and direct the post-transcriptional regulation of target mRNAs for degradation or translational repression via binding to the 3'UTRs and the coding exons. To gain insight into the biological role of miRNAs, it is essential to identify the full repertoire of mRNA targets (target genes). A number of computer programs have been developed for miRNA-target prediction. These programs essentially focus on potential binding sites in 3'UTRs, which are recognized by miRNAs according to specific base-pairing rules.
Results
Here, we introduce a novel method for miRNA-target prediction that is entirely independent of existing approaches. The method is based on the hypothesis that transcription of a miRNA and its target genes tend to be co-regulated by common transcription factors. This hypothesis predicts the frequent occurrence of common cis-elements between promoters of a miRNA and its target genes. That is, our proposed method first identifies putative cis-elements in a promoter of a given miRNA, and then identifies genes that contain common putative cis-elements in their promoters. In this paper, we show that a significant number of common cis-elements occur in ~28% of experimentally supported human miRNA-target data. Moreover, we show that the prediction of human miRNA-targets based on our method is statistically significant. Further, we discuss the random incidence of common cis-elements, their consensus sequences, and the advantages and disadvantages of our method.
Conclusions
This is the first report indicating prevalence of transcriptional regulation of a miRNA and its target genes by common transcription factors and the predictive ability of miRNA-targets based on this property.
doi:10.1186/1471-2164-14-S2-S3
PMCID: PMC3586946  PMID: 23445489
4.  MIR846 and MIR842 comprise a cistronic MIRNA pair that is regulated by abscisic acid by alternative splicing in roots of Arabidopsis 
Plant molecular biology  2013;81(4-5):447-460.
MicroRNAs (miRNAs) are ~21-nucleotide long endogenous small RNAs that regulate gene expression through post-transcriptional or transcriptional gene silencing (PTGS/TGS) and/or translational inhibition. miRNAs can arise from the “exon” of a MIRNA gene, from an intron (e.g. mirtrons in animals), or from the antisense strand of a protein coding gene (natural antisense microRNAs, nat-miRNAs). Here we demonstrate that two functionally related miRNAs, miR842 and miR846, arise from the same transcription unit but from alternate splicing isoforms. miR846 is expressed only from Isoform1 while in Isoforms2 and -3, a part of pre-miR846 containing the miRNA* sequence is included in the intron. The splicing of the intron truncates the pre-MIRNA and disrupts the expression of the mature miR846.. We name this novel phenomenon splicing-regulated miRNA. Abscisic acid (ABA) is shown to mediate the alternative splicing event by reducing the functional Isoform1 and increasing the non-functional Isoform3, thus repressing the expression of miR846 concomitant with accumulation of an ABA-inducible target jacalin At5g28520 mRNA, whose cleavage was shown by modified 5′-RACE. This regulation shows the functional importance of splicing-regulated miRNA and suggests possible mechanisms for altered ABA response phenotypes of miRNA biogenesis mutants. A. lyrata-MIR842 and Aly-MIR846 have conserved genomic arrangements with A. thaliana and candidate target jacalins, similar primary transcript structures and intron processing, and better miRNA-miRNA* pairings, suggesting that the interactions between ABA, MIR842, MIR846 and jacalins are similar in A. lyrata. Together, splicing-regulated miRNAs, nat-miRNAs/inc-miRNAs and mirtrons illustrate the complexity of MIRNA genes, the importance of introns in the biogenesis and regulation of miRNAs, and raise questions about the processes and molecular mechanisms that drive MIRNA evolution.
doi:10.1007/s11103-013-0015-6
PMCID: PMC3581712  PMID: 23341152
alternative splicing; microRNA; root; abscisic acid; plant development; pri-miRNA
5.  Primary microRNA transcript retention at sites of transcription leads to enhanced microRNA production 
The Journal of Cell Biology  2008;182(1):61-76.
MicroRNAs (miRNAs) are noncoding RNAs with important roles in regulating gene expression. In studying the earliest nuclear steps of miRNA biogenesis, we observe that primary miRNA (pri-miRNA) transcripts retained at transcription sites due to the deletion of 3′-end processing signals are converted more efficiently into precursor miRNAs (pre-miRNAs) than pri-miRNAs that are cleaved, polyadenylated, and released. Flanking exons, which also increase retention at transcription sites, likewise contribute to increased levels of intronic pri-miRNAs. Consistently, efficiently processed endogenous pri-miRNAs are enriched in chromatin-associated nuclear fractions. In contrast, pri-miRNAs that accumulate to high nuclear levels after cleavage and polyadenylation because of the presence of a viral RNA element (the ENE of the Kaposi's sarcoma–associated herpes virus polyadenylated nuclear RNA) are not efficiently processed to precursor or mature miRNAs. Exogenous pri-miRNAs unexpectedly localize to nuclear foci containing splicing factor SC35; yet these foci are unlikely to represent sites of miRNA transcription or processing. Together, our results suggest that pri-miRNA processing is enhanced by coupling to transcription.
doi:10.1083/jcb.200803111
PMCID: PMC2447899  PMID: 18625843
6.  MicroRNA in carcinogenesis & cancer diagnostics: A new paradigm 
MicroRNAs (miRNAs) are small 22-25 nucleotides long non-coding RNAs, that are conserved during evolution, and control gene expression in metazoan animals, plants, viruses, and bacteria primarily at post-transcriptional and transcriptional levels. MiRNAs ultimately regulate target gene expression by degrading the corresponding mRNA and/or inhibiting their translation. Currently, the critical functions of miRNAs have been established in regulating immune system, cell proliferation, differentiation and development, cancer and cell cycle by as yet unknown control mechanism. MiRNAs play an essential role in malignancy, and as tumour suppressors and oncogenes. Thus, discovery of new miRNAs will probably change the landscape of cancer genetics. Significantly different miRNA profiles can be assigned to various types of tumours, which could serve as phenotypic signatures for different cancers for their exploitation in cancer diagnostics, prognostics and therapeutics. If miRNA profiles can accurately predict malignancies, this technology could be exploited as a tool to surmount the diagnostic challenges. This review provides comprehensive and systematic information on miRNA biogenesis and their implications in human health.
PMCID: PMC3724248  PMID: 23703335
Biogenesis; cancer-gene expression; MicroRNA; oncogene
7.  dPORE-miRNA: Polymorphic Regulation of MicroRNA Genes 
PLoS ONE  2011;6(2):e16657.
Background
MicroRNAs (miRNAs) are short non-coding RNA molecules that act as post-transcriptional regulators and affect the regulation of protein-coding genes. Mostly transcribed by PolII, miRNA genes are regulated at the transcriptional level similarly to protein-coding genes. In this study we focus on human miRNAs. These miRNAs are involved in a variety of pathways and can affect many diseases. Our interest is on possible deregulation of the transcription initiation of the miRNA encoding genes, which is facilitated by variations in the genomic sequence of transcriptional control regions (promoters).
Methodology
Our aim is to provide an online resource to facilitate the investigation of the potential effects of single nucleotide polymorphisms (SNPs) on miRNA gene regulation. We analyzed SNPs overlapped with predicted transcription factor binding sites (TFBSs) in promoters of miRNA genes. We also accounted for the creation of novel TFBSs due to polymorphisms not present in the reference genome. The resulting changes in the original TFBSs and potential creation of new TFBSs were incorporated into the Dragon Database of Polymorphic Regulation of miRNA genes (dPORE-miRNA).
Conclusions
The dPORE-miRNA database enables researchers to explore potential effects of SNPs on the regulation of miRNAs. dPORE-miRNA can be interrogated with regards to: a/miRNAs (their targets, or involvement in diseases, or biological pathways), b/SNPs, or c/transcription factors. dPORE-miRNA can be accessed at http://cbrc.kaust.edu.sa/dpore and http://apps.sanbi.ac.za/dpore/. Its use is free for academic and non-profit users.
doi:10.1371/journal.pone.0016657
PMCID: PMC3033892  PMID: 21326606
8.  Regulation of miRNA biogenesis and turnover in the immune system 
Immunological reviews  2013;253(1):304-316.
Summary
MicroRNAs (miRNAs) have emerged as important regulators of gene expression in diverse biological processes ranging from cell proliferation and survival to organ development and immunity. Here, we review mechanisms that regulate the expression of miRNAs themselves in the immune system. Like protein-coding genes, miRNAs can be regulated at the transcriptional level, downstream of signaling pathways and circuits that activate or inhibit transcription factors and chromatin remodeling. The resulting primary miRNAs are processed into active mature miRNAs through a series of biochemical steps, and miRNA abundance can be regulated at each step of this biogenesis pathway. Recent work has uncovered regulation of mature miRNA turnover in the immune system as well. A better understanding of these processes and their regulation by immunogenic stimuli is critical for integrating miRNAs into current models of gene expression networks that determine cell identity and immune function.
doi:10.1111/imr.12059
PMCID: PMC3621012  PMID: 23550654
miRNA processing; miRNA turnover; Argonaute
9.  Regulatory coordination of clustered microRNAs based on microRNA-transcription factor regulatory network 
BMC Systems Biology  2011;5:199.
Background
MicroRNA (miRNA) is a class of small RNAs of ~22nt which play essential roles in many crucial biological processes and numerous human diseases at post-transcriptional level of gene expression. It has been revealed that miRNA genes tend to be clustered, and the miRNAs organized into one cluster are usually transcribed coordinately. This implies a coordinated regulation mode exerted by clustered miRNAs. However, how the clustered miRNAs coordinate their regulations on large scale gene expression is still unclear.
Results
We constructed the miRNA-transcription factor regulatory network that contains the interactions between transcription factors (TFs), miRNAs and non-TF protein-coding genes, and made a genome-wide study on the regulatory coordination of clustered miRNAs. We found that there are two types of miRNA clusters, i.e. homo-clusters that contain miRNAs of the same family and hetero-clusters that contain miRNAs of various families. In general, the homo-clustered as well as the hetero-clustered miRNAs both exhibit coordinated regulation since the miRNAs belonging to one cluster tend to be involved in the same network module, which performs a relatively isolated biological function. However, the homo-clustered miRNAs show a direct regulatory coordination that is realized by one-step regulation (i.e. the direct regulation of the coordinated targets), whereas the hetero-clustered miRNAs show an indirect regulatory coordination that is realized by a regulation comprising at least three steps (e.g. the regulation on the coordinated targets by a miRNA through a sequential action of two TFs). The direct and indirect regulation target different categories of genes, the former predominantly regulating genes involved in emergent responses, the latter targeting genes that imply long-term effects.
Conclusion
The genomic clustering of miRNAs is closely related to the coordinated regulation in the gene regulatory network. The pattern of regulatory coordination is dependent on the composition of the miRNA cluster. The homo-clustered miRNAs mainly coordinate their regulation rapidly, while the hetero-clustered miRNAs exert control with a delay. The diverse pattern of regulatory coordination suggests distinct roles of the homo-clustered and the hetero-clustered miRNAs in biological processes.
doi:10.1186/1752-0509-5-199
PMCID: PMC3262773  PMID: 22176772
10.  Advances in the Techniques for the Prediction of microRNA Targets 
MicroRNAs (miRNAs) are small, non-coding, endogenous RNA molecules that play important roles in a variety of normal and diseased biological processes by post-transcriptionally regulating the expression of target genes. They can bind to target messenger RNA (mRNA) transcripts of protein-coding genes and negatively control their translation or cause mRNA degradation. miRNAs have been found to actively regulate a variety of cellular processes, including cell proliferation, death, and metabolism. Therefore, their study is crucial for the better understanding of cellular functions in eukaryotes. To better understand the mechanisms of miRNA: mRNA interaction and their cellular functions, it is important to identify the miRNA targets accurately. In this paper, we provide a brief review for the advances in the animal miRNA target prediction methods and available resources to facilitate further study of miRNAs and their functions.
doi:10.3390/ijms14048179
PMCID: PMC3645737  PMID: 23591837
prediction; microRNA; feature selection
11.  Control of microRNA Biogenesis by TGFβ Signaling Pathway ----a novel role of Smads in the nucleus 
Cytokine & growth factor reviews  2009;20(5-6):517-521.
microRNAs (miRNAs) are small, non-coding RNAs that modulate diverse biological functions through the repression of target genes. miRNA profiling studies have indicated that the levels of miRNAs are altered during normal development and pathogenesis of various diseases, including cancer and cardiovascular disorders. The signaling pathways which control miRNA biogenesis and the mechanisms of regulation, however, are not well understood. Following transcription, mature miRNAs are generated through a series of coordinated processing events mediated by large protein complexes. We recently found that signal transducers of the Transforming Growth Factor β (TGFβ) signaling pathway, the Smads, play a regulatory role in the processing of miRNA in the nucleus. In this review, we summarize the current understanding of the regulation of miRNA biogenesis mediated by the TGFβ signaling pathway.
doi:10.1016/j.cytogfr.2009.10.004
PMCID: PMC2787811  PMID: 19892582
12.  Inter- and intra-combinatorial regulation by transcription factors and microRNAs 
BMC Genomics  2007;8:396.
Background
MicroRNAs (miRNAs) are a novel class of non-coding small RNAs. In mammalian cells, miRNAs repress the translation of messenger RNAs (mRNAs) or degrade mRNAs. miRNAs play important roles in development and differentiation, and they are also implicated in aging, and oncogenesis. Predictions of targets of miRNAs suggest that they may regulate more than one-third of all genes. The overall functions of mammalian miRNAs remain unclear. Combinatorial regulation by transcription factors alone or miRNAs alone offers a wide range of regulatory programs. However, joining transcriptional and post-transcriptional regulatory mechanisms enables higher complexity regulatory programs that in turn could give cells evolutionary advantages. Investigating coordinated regulation of genes by miRNAs and transcription factors (TFs) from a statistical standpoint is a first step that may elucidate some of their roles in various biological processes.
Results
Here, we studied the nature and scope of coordination among regulators from the transcriptional and miRNA regulatory layers in the human genome. Our findings are based on genome wide statistical assessment of regulatory associations ("interactions") among the sets of predicted targets of miRNAs and sets of putative targets of transcription factors. We found that combinatorial regulation by transcription factor pairs and miRNA pairs is much more abundant than the combinatorial regulation by TF-miRNA pairs. In addition, many of the strongly interacting TF-miRNA pairs involve a subset of master TF regulators that co-regulate genes in coordination with almost any miRNA. Application of standard measures for evaluating the degree of interaction between pairs of regulators show that strongly interacting TF-miRNA, TF-TF or miRNA-miRNA pairs tend to include TFs or miRNAs that regulate very large numbers of genes. To correct for this potential bias we introduced an additional Bayesian measure that incorporates not only how significant an interaction is but also how strong it is. Putative pairs of regulators selected by this procedure are more likely to have biological coordination. Importantly, we found that the probability of a TF-miRNA pair forming feed forward loops with its common target genes (where the miRNA simultaneously suppresses the TF and many of its targets) is increased for strongly interacting TF-miRNA pairs.
Conclusion
Genes are more likely to be co-regulated by pairs of TFs or pairs of miRNAs than by pairs of TF-miRNA, perhaps due to higher probability of evolutionary duplication events of shorter DNA sequences. Nevertheless, many gene sets are reciprocally regulated by strongly interacting pairs of TF-miRNA, which suggests an effective mechanism to suppress functionally related proteins. Moreover, the particular type of feed forward loop (with two opposing modes where the TF activates its target genes or the miRNA simultaneously suppresses this TF and the TF-miRNA joint target genes) is more prevalent among strongly interacting TF-miRNA pairs. This may be attributed to a process that prevents waste of cellular resources or a mechanism to accelerate mRNA degradation.
doi:10.1186/1471-2164-8-396
PMCID: PMC2206040  PMID: 17971223
13.  Identification of phylogenetically conserved sequence motifs in microRNA 5' flanking sites from C. elegans and C. briggsae 
BMC Molecular Biology  2008;9:105.
Background
MicroRNAs (miRNAs) are small, noncoding RNA molecules that act as post-transcriptional regulators of gene expression. Studies concerning transcriptional regulation of miRNAs have so far concentrated on those located within the intergenic region of the genome and the search for putative promoters, thus leaving open the question of the existence of possible regulatory elements common to all miRNAs including those located in introns of protein coding genes.
Results
In this study, we initially searched for motifs occurring in the area 1000 bp upstream from all miRNAs independent of their genomic location. We discovered a previously unknown sequence motif GANNNNGA that displayed a conserved distribution in the nematode worms Caenorhabditis elegans and Caenorhabditis briggsae. This motif had a peak occurrence at 500 bp upstream, with a sharp drop-off toward the miRNA start site. Further analysis indicated that this motif was locally restricted and not enriched 1000–5000 bp upstream or 0–2000 bp downstream of the miRNA start site. In addition, this motif was observed to be most abundant in the upstream sequences of two important miRNAs, mir-1 and mir-124. This abundance was also conserved in phylogenetically distant species including human and mouse.
Conclusion
The results show that the motif GANNNNGA is conserved close to miRNA precursor start sites, suggesting that it may be involved in miRNA sequence recognition or regulation. This data provides important knowledge for the identification and computational prediction of miRNA sequences.
doi:10.1186/1471-2199-9-105
PMCID: PMC2613404  PMID: 19036124
14.  Transcripts for combined synthetic microRNA and gene delivery 
Molecular bioSystems  2013;9(7):1919-1925.
MicroRNAs (miRNAs) are a class of short noncoding RNAs which are endogenously expressed in many organisms and regulate gene expression by binding to messenger RNA (mRNA). MiRNAs are either produced from their independent transcription units in intergenic regions or lie in intragenic regions. Intragenic miRNAs and their host mRNAs are produced from the same transcript by the microprocessor and the spliceosome protein complex respectively. The details and exact timing of the processing events have implications to downstream RNA interference (RNAi) efficiency and mRNA stability. Here we engineer and study in mammalian cells a range of synthetic intragenic miRNAs co-expressed with their host genes. Furthermore, we study transcripts which carry the target of the miRNA, thereby emulating a common regulation mechanism. We perform fluorescence microscopy and flow cytometry to characterize the engineered transcripts and investigate the properties of the underlying biological processes. Our results shed additional light on miRNA and pre-mRNA processing but importantly provide insight towards engineering transcripts customized for combined delivery and use in synthetic gene circuits.
doi:10.1039/c3mb70043g
PMCID: PMC3674133  PMID: 23579254
15.  Endogenous TasiRNAs Mediate Non-Cell Autonomous Effects on Gene Regulation in Arabidopsis thaliana 
PLoS ONE  2009;4(6):e5980.
Background
Different classes of small RNAs (sRNAs) refine the expression of numerous genes in higher eukaryotes by directing protein partners to complementary nucleic acids, where they mediate gene silencing. Plants encode a unique class of sRNAs, called trans-acting small interfering RNAs (tasiRNAs), which post-transcriptionally regulate protein-coding transcripts, as do microRNAs (miRNAs), and both sRNA classes control development through their targets. TasiRNA biogenesis requires multiple components of the siRNA pathway and also miRNAs. But while 21mer siRNAs originating from transgenes can mediate silencing across several cell layers, miRNA action seems spatially restricted to the producing or closely surrounding cells.
Principal Findings
We have previously described the isolation of a genetrap reporter line for TAS3a, the major locus producing AUXIN RESPONS FACTOR (ARF)-regulating tasiRNAs in the Arabidopsis shoot. Its activity is limited to the adaxial (upper) side of leaf primordia, thus spatially isolated from ARF-activities, which are located in the abaxial (lower) side. We show here by in situ hybridization and reporter fusions that the silencing activities of ARF-regulating tasiRNAs are indeed manifested non-cell autonomously to spatially control ARF activities.
Conclusions/Significance
Endogenous tasiRNAs are thus mediators of a mobile developmental signal and might provide effective gene silencing at a distance beyond the reach of most miRNAs.
doi:10.1371/journal.pone.0005980
PMCID: PMC2694355  PMID: 19543387
16.  Therapeutic MicroRNA Strategies in Human Cancer 
The AAPS Journal  2009;11(4):747-757.
MicroRNAs (miRNAs) are ~22 nucleotide long, noncoding, endogenous RNA molecules which exert their functions by base pairing with messenger RNAs (mRNAs), thereby regulate protein-coding gene expression. In eukaryotic cells, miRNAs play important roles in regulating biological processes such as proliferation, differentiation, apoptosis, and stem cell self-renewal. The human genome may contain as many as 1,000 miRNAs, and more than 700 of them have been identified. miRNAs are predicted to target up to one third of mRNAs. Each miRNA can target hundreds of transcripts directly or indirectly, while more than one miRNA can converge on a single transcript target. Therefore, the potential regulatory circuitry afforded by miRNA is enormous. Recently, mounting evidence implicates miRNAs as a new class of modulator for human tumor initiation and progression. Therefore, it has been proposed that manipulating miRNA activity and miRNA biogenesis may be a novel avenue for developing efficient therapies against cancer.
doi:10.1208/s12248-009-9145-9
PMCID: PMC2782079  PMID: 19876744
cancer; microRNA; noncoding RNA; therapy
17.  PMRD: plant microRNA database 
Nucleic Acids Research  2009;38(Database issue):D806-D813.
MicroRNAs (miRNA) are ∼21 nucleotide-long non-coding small RNAs, which function as post-transcriptional regulators in eukaryotes. miRNAs play essential roles in regulating plant growth and development. In recent years, research into the mechanism and consequences of miRNA action has made great progress. With whole genome sequence available in such plants as Arabidopsis thaliana, Oryza sativa, Populus trichocarpa, Glycine max, etc., it is desirable to develop a plant miRNA database through the integration of large amounts of information about publicly deposited miRNA data. The plant miRNA database (PMRD) integrates available plant miRNA data deposited in public databases, gleaned from the recent literature, and data generated in-house. This database contains sequence information, secondary structure, target genes, expression profiles and a genome browser. In total, there are 8433 miRNAs collected from 121 plant species in PMRD, including model plants and major crops such as Arabidopsis, rice, wheat, soybean, maize, sorghum, barley, etc. For Arabidopsis, rice, poplar, soybean, cotton, medicago and maize, we included the possible target genes for each miRNA with a predicted interaction site in the database. Furthermore, we provided miRNA expression profiles in the PMRD, including our local rice oxidative stress related microarray data (LC Sciences miRPlants_10.1) and the recently published microarray data for poplar, Arabidopsis, tomato, maize and rice. The PMRD database was constructed by open source technology utilizing a user-friendly web interface, and multiple search tools. The PMRD is freely available at http://bioinformatics.cau.edu.cn/PMRD. We expect PMRD to be a useful tool for scientists in the miRNA field in order to study the function of miRNAs and their target genes, especially in model plants and major crops.
doi:10.1093/nar/gkp818
PMCID: PMC2808885  PMID: 19808935
18.  MicroRNA biogenesis: Regulating the Regulators 
MicroRNAs (miRNAs) function as 21–24 nucleotide guide RNAs that use partial base-pairing to recognize target messenger RNAs and repress their expression. As a large fraction of protein-coding genes are under miRNA control, production of the appropriate level of specific miRNAs at the right time and in the right place is integral to most gene regulatory pathways. MiRNA biogenesis initiates with transcription, followed by multiple processing steps to produce the mature miRNA. Every step of miRNA production is subject to regulation and disruption of these control mechanisms has been linked to numerous human diseases, where the balance between the expression of miRNAs and their targets becomes distorted. Here we review the basic steps of miRNA biogenesis and describe the various factors that control miRNA transcription, processing and stability in animal cells. The tremendous effort put into producing the appropriate type and level of specific miRNAs underscores the critical role of these small RNAs in gene regulation.
doi:10.3109/10409238.2012.738643
PMCID: PMC3557704  PMID: 23163351
miRNA; Dicer; Drosha; Argonaute; mirtron
19.  MicroRNAs and neuronal development 
Summary
The importance of the involvement of non-protein coding RNAs in biological processes has become evident in recent years along with the identification of the transcriptional regulatory mechanisms that allow them to exert their roles. MicroRNAs (miRNAs) are a novel class of small non-coding RNA that regulates messenger RNA abundance. The capacity of each miRNA to target several transcripts suggests an ability to build a complex regulatory network for fine tuning gene expression; a mechanism by which they are thought to regulate cell fate, proliferation and identity. The brain expresses more distinct miRNAs than any other tissue in vertebrates and it presents an impressive variety of cell types, including many different classes of neurons. Here we review more than 10 years of miRNA research, and discuss the most important findings that have established miRNAs as key regulators of neuronal development.
doi:10.1016/j.siny.2012.07.008
PMCID: PMC3490020  PMID: 22906916
Development; Differentiation; Gene expression; MicroRNA; Neurons
20.  UV-B responsive microRNA genes in Arabidopsis thaliana 
MicroRNAs (miRNAs) are small, non-coding RNAs that play critical roles in post-transcriptional gene regulation. In plants, mature miRNAs pair with complementary sites on mRNAs and subsequently lead to cleavage and degradation of the mRNAs. Many miRNAs target mRNAs that encode transcription factors; therefore, they regulate the expression of many downstream genes. In this study, we carry out a survey of Arabidopsis microRNA genes in response to UV-B radiation, an important adverse abiotic stress. We develop a novel computational approach to identify microRNA genes induced by UV-B radiation and characterize their functions in regulating gene expression. We report that in A. thaliana, 21 microRNA genes in 11 microRNA families are upregulated under UV-B stress condition. We also discuss putative transcriptional downregulation pathways triggered by the induction of these microRNA genes. Moreover, our approach can be directly applied to miRNAs responding to other abiotic and biotic stresses and extended to miRNAs in other plants and metazoans.
doi:10.1038/msb4100143
PMCID: PMC1865585  PMID: 17437028
integration of heterogeneous data; microRNA gene; UV-B responsive
21.  Smad-mediated miRNA processing 
RNA Biology  2011;8(1):71-76.
microRNAs (miRNAs) are short, 21–24 nucleotide (nt), non-coding RNAs that post-transcriptionally regulate the expression of messenger RNAs (mRNAs). Through the regulation of their cognate mRNAs, miRNAs control diverse aspects of biology, including development, cellular differentiation, proliferation, metabolism and death. Thus, miRNAs play a critical role in the determination of normal cellular physiology and misexpression of miRNAs leads to pathological responses. Understanding the mechanisms that control miRNA expression is an important step forward as novel functions of miRNAs continue to be uncovered. In addition to transcriptional regulation, multiple pathways of post-transcriptional modulation of miRNA expression have been uncovered. In this review we discuss the role of the Smads in the regulation of miRNA processing in response to Transforming growth factor β (TGFβ) stimulation.
doi:10.4161/rna.8.1.14299
PMCID: PMC3230544  PMID: 21289485
microRNA; miRNA; TGFβ; BMP; smads; biogenesis; drosha; processing
22.  Annotation of mammalian primary microRNAs 
BMC Genomics  2008;9:564.
Background
MicroRNAs (miRNAs) are important regulators of gene expression and have been implicated in development, differentiation and pathogenesis. Hundreds of miRNAs have been discovered in mammalian genomes. Approximately 50% of mammalian miRNAs are expressed from introns of protein-coding genes; the primary transcript (pri-miRNA) is therefore assumed to be the host transcript. However, very little is known about the structure of pri-miRNAs expressed from intergenic regions. Here we annotate transcript boundaries of miRNAs in human, mouse and rat genomes using various transcription features. The 5' end of the pri-miRNA is predicted from transcription start sites, CpG islands and 5' CAGE tags mapped in the upstream flanking region surrounding the precursor miRNA (pre-miRNA). The 3' end of the pri-miRNA is predicted based on the mapping of polyA signals, and supported by cDNA/EST and ditags data. The predicted pri-miRNAs are also analyzed for promoter and insulator-associated regulatory regions.
Results
We define sets of conserved and non-conserved human, mouse and rat pre-miRNAs using bidirectional BLAST and synteny analysis. Transcription features in their flanking regions are used to demarcate the 5' and 3' boundaries of the pri-miRNAs. The lengths and boundaries of primary transcripts are highly conserved between orthologous miRNAs. A significant fraction of pri-miRNAs have lengths between 1 and 10 kb, with very few introns. We annotate a total of 59 pri-miRNA structures, which include 82 pre-miRNAs. 36 pri-miRNAs are conserved in all 3 species. In total, 18 of the confidently annotated transcripts express more than one pre-miRNA. The upstream regions of 54% of the predicted pri-miRNAs are found to be associated with promoter and insulator regulatory sequences.
Conclusion
Little is known about the primary transcripts of intergenic miRNAs. Using comparative data, we are able to identify the boundaries of a significant proportion of human, mouse and rat pri-miRNAs. We confidently predict the transcripts including a total of 77, 58 and 47 human, mouse and rat pre-miRNAs respectively. Our computational annotations provide a basis for subsequent experimental validation of predicted pri-miRNAs.
doi:10.1186/1471-2164-9-564
PMCID: PMC2632650  PMID: 19038026
23.  MicroRNA and Cancer Chemoprevention 
MicroRNAs (miRNAs) are a group of naturally occurring, small, non-coding, and single-strand RNA molecules that regulate gene expression at the post-transcriptional and translational levels. By controlling the expression of oncogenic and tumor suppressor proteins, miRNAs are believed to play an important role in pathological processes associated with malignant progression including tumor cell proliferation, apoptosis, differentiation, angiogenesis, invasion and metastasis. However, relatively few studies have investigated the influence of chemopreventive agents on miRNA expression and their regulation of target genes. Given the significance of miRNAs in modulating gene expression, such research can provide insight into the pleiotropic biological effects that chemopreventive agents often display and a deeper understanding of their mechanism of action to inhibit carcinogenesis. Additionally, miRNAs can provide useful biomarkers for assessing antineoplastic activity of these agents in preclinical and clinical observations. In this review, we summarize recent publications that highlight a potentially important role of miRNAs in cancer chemoprevention research.
doi:10.1158/1940-6207.CAPR-13-0032
PMCID: PMC3644360  PMID: 23531448
microRNA; chemoprevention; cancer
24.  Identification of Novel miRNAs and miRNA Dependent Developmental Shifts of Gene Expression in Arabidopsis thaliana 
PLoS ONE  2010;5(4):e10157.
microRNAs (miRNAs) are small, endogenous RNAs of 20∼25 nucleotides, processed from stem-loop regions of longer RNA precursors. Plant miRNAs act as negative regulators of target mRNAs predominately by slicing target transcripts, and a number of miRNAs play important roles in development. We analyzed a number of published datasets from Arabidopsis thaliana to characterize novel miRNAs, novel miRNA targets, and miRNA-regulated developmental changes in gene expression. These data include microarray profiling data and small RNA (sRNA) deep sequencing data derived from miRNA biogenesis/transport mutants, microarray profiling data of mRNAs in a developmental series, and computational predictions of conserved genomic stem-loop structures. Our conservative analyses identified five novel mature miRNAs and seven miRNA targets, including one novel target gene. Two complementary miRNAs that target distinct mRNAs were encoded by one gene. We found that genes targeted by known miRNAs, and genes up-regulated or down-regulated in miRNA mutant inflorescences, are highly expressed in the wild type inflorescence. In addition, transcripts upregulated within the mutant inflorescences were abundant in wild type leaves and shoot meristems and low in pollen and seed. Downregulated transcripts were abundant in wild type pollen and seed and low in shoot meristems, roots and leaves. Thus, disrupting miRNA function causes the inflorescence transcriptome to resemble the leaf and meristem and to differ from pollen and seed. Applications of our computational approach to other species and the use of more liberal criteria than reported here will further expand the number of identified miRNAs and miRNA targets. Our findings suggest that miRNAs have a global role in promoting vegetative to reproductive transitions in A. thaliana.
doi:10.1371/journal.pone.0010157
PMCID: PMC2854152  PMID: 20405016
25.  MicroRNAs, diet, and cancer: new mechanistic insights on the epigenetic actions of phytochemicals 
Molecular Carcinogenesis  2011;51(3):213-230.
There is growing interest in the epigenetic mechanisms that impact human health and disease, including the role of microRNAs (miRNAs). These small (18–25 nucleotide), evolutionarily conserved, non-coding RNA molecules regulate gene expression in a post-transcriptional manner. Several well-orchestered regulatory mechanisms involving miRNAs have been identified, with the potential to target multiple signaling pathways dysregulated in cancer. Since the initial discovery of miRNAs, there has been progress towards therapeutic applications, and several natural and synthetic chemopreventive agents also have been evaluated as modulators of miRNA expression in different cancer types. This review summarizes the most up-to-date information related to miRNA biogenesis, and critically evaluates proposed miRNA regulatory mechanisms in relation to cancer signaling pathways, as well as other epigenetic modifications (DNA methylation patterns, histone marks) and their involvement in drug resistance. We also discuss the mechanisms by which dietary factors regulate miRNA expression, in the context of chemoprevention versus therapy.
doi:10.1002/mc.20822
PMCID: PMC3196802  PMID: 21739482

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