Intronic microRNAs

doi:10.1016/j.bbrc.2004.10.215

Biochemical and Biophysical Research Communications

Volume 326, Issue 3, 21 January 2005, Pages 515-520

https://doi.org/10.1016/j.bbrc.2004.10.215 Get rights and content

Abstract

MicroRNAs (miRNAs), small single-stranded regulatory RNAs capable of interfering with intracellular mRNAs that contain partial complementarity, are useful for the design of new therapies against cancer polymorphism and viral mutation. MiRNA was originally discovered in the intergenic regions of the Caenorhabditis elegans genome as native RNA fragments that modulate a wide range of genetic regulatory pathways during animal development. However, neither RNA promoter nor polymerase responsible for miRNA biogenesis was determined. Recent findings of intron-derived miRNA in C. elegans, mouse, and human have inevitably led to an alternative pathway for miRNA biogenesis, which relies on the coupled interaction of Pol-II-mediated pre-mRNA transcription and intron excision, occurring in certain nuclear regions proximal to genomic perichromatin fibrils.

Section snippets

Alternative miRNA biogenesis by intron processing: intronic miRNA genes

Some miRNAs have recently been identified to be intron-derived. The precursor mRNA (pre-mRNA) is the primary transcript of a gene and is a long, single-stranded RNA molecule containing both protein-coding exons and non-coding introns. The introns must be removed by splicing processes and the exons are ligated together to form a mature mRNA for protein synthesis. This reduction in length of the pre-mRNA by RNA splicing involves spliceosomes, complexes of five small nuclear ribonucleoprotein

Conclusion

A comprehensive encyclopedia of intron functions is needed to utilize the genome fully to establish a better understanding of human biological processes, to predict potential disease risks, and to stimulate the development of new therapies and interventions to prevent and treat diseases. Treatments based on such an intron-mediated RNAi system can advance current therapeutical design and provide a safer means for gene therapy since intron-derived miRNA production is tightly regulated by

Acknowledgment

The research is supported by National Institute of Health/National Cancer Institute Grant R01 CA-85722.

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Citation Excerpt :
Intronic miRNAs exhibit the following four characteristics: i) they and their encoding gene transcripts must share the same promoter, ii) their location must be in the non-protein-coding region of a primary gene transcript, iii) they and the gene transcripts are coexpressed, and iv) in order to form mature miRNAs, the nuclear RNA splicing and excision processes must remove them from the transcripts of their coding genes. Many of the miRNAs that are to be discussed later are oriented oppositely to the protein-coding gene transcript meaning that they are not intronic miRNAs given that they don't share a promoter with the gene; with these miRNAs, their promoters are situated in the antisense orientation to the gene [5, 6, 7]. In eukaryotes, intronic and other ncRNAs have possibly evolved to give a second level gene expression.
MiRNAs are naturally occurring, small, non-coding RNA molecules that post-transcriptionally regulate the expression of a large number of genes involved in various biological processes, either through mRNA degradation or through translation inhibition. MiRNAs play important roles in many aspects of physiology and pathology throughout the body, particularly in cancer, which have made miRNAs attractive tools and targets for translational research. The types of non-coding RNAs, biogenesis of miRNAs, circulating miRNAs, and direct delivery of miRNA were briefly reviewed. As a case of point, the role and perspective of miR-302, a family of ES-specific miRNA, on cancer, iPSCs, heart disease were presented.
The role of introns in the conservation of the metabolic genes of Arabidopsis thaliana
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Citation Excerpt :
Some introns also regulate gene expression [5]. Moreover, introns play a pivotal role in mRNA export, transcription coupling, splicing, etc. [21] and also give rise to non-coding RNAs that participate in regulatory processes [22]. Introns can also boost the gene expression, and this positive effect is called intron-mediated enhancement (IME) [23].
In Arabidopsis thaliana, primary metabolic genes (PMGs) are more evolutionarily conserved and intron-rich than secondary metabolic genes. We observed that PMGs are more primitive and pan-taxonomically persistent as compared to secondary (SMGs) and non-metabolic genes (NMGs). This difference in primitiveness and persistence is primarily correlated with intron number and is independent of gene expression level. We propose a twofold explanation behind higher intron enrichment in PMGs. Firstly, introns might increase protein versatility amongst PMGs through alternative splicing, providing selective advantage of PMGs and making them more persistent across diverse plant taxa. Also, multifunctional PMGs may acquire functional domains by increasing the intronic burden. Additionally, single nucleotide polymorphisms (SNPs) accumulate at a higher rate in introns as compared to exons. Moreover, a strong negative correlation between cumulative exonic SNPs density and intron number indicates that introns may protect the exonic regions against the deleterious effect of these mutations, making them more conserved.
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Long non-coding RNAs (LncRNAs) are abundant in the genome of higher forms of eukaryotes and implicated in regulating the diversity of biological processes partly because they host microRNAs (miRNAs), which are repressors of target gene expression. In vertebrates, miR-133 regulates the differentiation and proliferation of cardiac and skeletal muscles. Pinctada martensii miR-133 (pm-miR-133) was identified in our previous research through Solexa deep sequencing. In the present study, the precise sequence of mature pm-miR-133 was validated through miR-RACE. Stem loop qRT-PCR analysis demonstrated that mature pm-miR-133 was constitutively expressed in the adductor muscle, gonad, hepatopancreas, mantle, foot, and gill of P. martensii. Among these tissues, the adductor muscle exhibited the highest pm-miR-133 expression. Target analysis indicated that pm-RhoA was the potential regulatory target of pm-miR-133. Bioinformatics analyses revealed that a potential LncRNA (designated as Lnc133) with a mature pm-miR-133 could generate a hairpin structure that was highly homologous to that of Lottia gigantea. Lnc133 was also highly expressed in the adductor muscle, gill, hepatopancreas, and gonad. Phylogenetic analysis further showed that the miR-133s derived from chordate and achordate were separated into two classes. Therefore, Lnc133 hosting pm-miR-133 could be involved in regulating the cell proliferation of adductor muscles by targeting pm-RhoA.
Microsynteny and phylogenetic analysis of tandemly organised miRNA families across five members of Brassicaceae reveals complex retention and loss history
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Citation Excerpt :
MicroRNAs (miRNAs) are 20–24 nucleotide long noncoding RNAs that regulate target gene expression at various levels via target cleavage, interference with translation or chromatin re-organisation [3–5]. MiRNAs are usually encoded by discrete genomic loci that lie between other protein and non-protein coding genes; in animal systems, intronic encoded miRNAs, known as miRTrons have also been discovered [6,7]. MiRNA genes are regulated by type II promoters and are transcribed by RNA polymerase II [8] or rarely also RNA pol III [9].
Plant genomes are characterized by the presence of large miRNA gene families which are few in number. The expansion of miRNA families is thought to be driven by gene and genome duplication. Some members of these miRNA gene families are tandemly arranged and their analysis is of interest because such organisation may indicate origin through tandem duplication and also to investigate whether some such tandem clusters have similar expression patterns, and whether these are regulated through a common set of cis-regulatory elements (eg. promoters and enhancers). As a first step, we undertake a comprehensive study using micro-synteny analyses of tandemly organised miRNA families across the Brassicaceae spanning an evolutionary time scale of ca. 45 million years, among Arabidopsis, Capsella, Brassica and Thellungiella species, to address the following questions: Are most miRNA gene families present as tandem clusters? To what extent are these tandem patterns retained? To what extent can family sizes be ascribed to genome duplication? Our analysis of thirteen tandemly organised miRNA families revealed that synteny is largely conserved among Arabidopsis thaliana, A. lyrata and Capsella rubella, which form a clade spanning approximately between 6.2–9.8 my (Acarkan et al., 2000) [1]. On the other hand, comparison of sequences from these species with Brassica rapa, B. oleracea and Thellungiella halophila, which form a separate clade spanning 31 my (Franzke et al., 2011) [2] reveals many differences. The latter clade reveals several paralogous duplications that probably resulted from whole genome duplication, as well as disrupted synteny. Phylogenetic analyses of precursor sequences generally support the history inferred from synteny analysis. Synteny and phylogenetic analysis of six members of the tandemly organised miR169 family suggest that the Brassicaceae ancestral state consisted of a “dimer as a unit” which may have undergone direct local duplication to retain the transcriptional orientation followed by lineage specific changes. MiR169, to the best of our knowledge, is one of the largest tandemly organised miRNA gene family across plant kingdom and further analysis should reveal the generality of this pattern of evolution. The conserved organisation of miR395A-B-C and miR395 D-E-F as two clusters on same chromosome/scaffold across A. thaliana, B. rapa and salsuginea demonstrates retention of the large chromosomal segment across the two lineages. MiRNA family miR845 was detected only in Arabidopsis species and Thellungiella indicating a complex loss and retention history. MiR447A-B family was only found in A. thaliana indicating that it is a species-specific gene family of recent origin.
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MicroRNAs are short noncoding RNA molecules that regulate gene expression at the post-transcriptional level. Like DNA methylation and histone modification, miRNA activity epigenetically regulates the expression of various protein-encoding genes. To date over 10,000 miRNAs have been identified, of which 940 are human. It is estimated that more than 60% of human protein-coding genes harbor miRNA target sites and thus are potentially regulated by these molecules. Mounting evidence suggests that miRNAs are involved in cell reprogramming and therefore their aberrant expression is associated with pathophysiological processes such as cancer and other disease states.

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Biochemical and Biophysical Research Communications

Abstract

Section snippets

Alternative miRNA biogenesis by intron processing: intronic miRNA genes

Conclusion

Acknowledgment

References (21)

Message and non-message sequences adjacent to poly(A) in steady state heterogeneous nuclear RNA of HeLa cells

Cell

A novel RNA splicing-mediated gene silencing mechanism potential for genome evolution

Biochem. Biophys. Res. Commun.

MicroRNAs and other tiny endogenous RNAs in C. elegans

Curr. Biol.

MicroRNAs: genomics, biogenesis, mechanism, and function

Cell

A Novel mRNA-cDNA interference phenomenon for silencing bcl-2 expression in human LNCaP cells

Biochem. Biophys. Res. Commun.

RNA interference and mRNA silencing, 2004: how far will they reach?

Mol. Biol. Cell

A quantitative analysis of intron effects on mammalian gene expression

RNA

Localization of pre-mRNA splicing in mammalian nuclei

Nature

Coupled in vitro synthesis and splicing of RNA polymerase II transcripts

RNA

Identification of virus-encoded microRNAs

Science

Cited by (92)

Epigenetic Modification of MicroRNAs

The microRNA and the perspectives of miR-302

The role of introns in the conservation of the metabolic genes of Arabidopsis thaliana

Pm-miR-133 hosting in one potential lncRNA regulates RhoA expression in pearl oyster Pinctada martensii

Microsynteny and phylogenetic analysis of tandemly organised miRNA families across five members of Brassicaceae reveals complex retention and loss history

Epigenetic Modification of MicroRNAs

Breakthroughs and ViewsIntronic microRNAs

Abstract

Section snippets

Alternative miRNA biogenesis by intron processing: intronic miRNA genes

Conclusion

Acknowledgment

Cell

Biochem. Biophys. Res. Commun.

Curr. Biol.

Cell

Biochem. Biophys. Res. Commun.

RNA interference and mRNA silencing, 2004: how far will they reach?

Mol. Biol. Cell

A quantitative analysis of intron effects on mammalian gene expression

RNA

Localization of pre-mRNA splicing in mammalian nuclei

Nature

Coupled in vitro synthesis and splicing of RNA polymerase II transcripts

RNA

Identification of virus-encoded microRNAs

Science

Breakthroughs and Views
Intronic microRNAs