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 Table of Contents  
REVIEW
Year : 2015  |  Volume : 1  |  Issue : 4  |  Page : 137-152

Functional Perspective and Implications of Gene Expression by Noncoding RNAs


1 School of Medicine, Shanghai Jiao Tong University, Shanghai, China
2 Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
3 Division of Nephrology, College of Physicians and Surgeons, Columbia University, New York, NY, USA

Date of Submission15-Jul-2015
Date of Acceptance07-Aug-2015
Date of Web Publication27-Aug-2015

Correspondence Address:
Zhonghai Yan
Division of Nephrology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2395-3977.163805

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  Abstract 

Noncoding RNAs (ncRNAs) have gained widespread attention in recent years as a potentially new and crucial tool in biological regulation. Although they have been associated with a range of developmental processes and diseases, knowledge of the mechanisms by which they act is still surprisingly limited. To claim that almost entire mammalian genome is transcribed into functional noncoding transcripts remain controversial. Nevertheless, a small number of well executed studies on ncRNAs have given us important clues concerning the biological function of these molecules, and have successfully uncovered a few of their key functional and mechanistic themes, although the robustness of these models and classification schemes remains to be elucidated. Here, we summarize the new insights into ncRNAs field, discussing what is known about the genomic contexts, biological functions in human cancer, neural system disorders, stem cell (SC) self-renewal, and mechanisms of action of ncRNAs. Meanwhile, we have also tried to shed light on how the recent interest in ncRNAs is deeply rooted in biology's longstanding concern of the evolution and function of genomes.

Keywords: Cancer, central nervous system disorders, diabetes, long noncoding RNAs, microRNAs, noncoding RNAs, pluripotency


How to cite this article:
Yan X, Xu H, Yan Z. Functional Perspective and Implications of Gene Expression by Noncoding RNAs. Cancer Transl Med 2015;1:137-52

How to cite this URL:
Yan X, Xu H, Yan Z. Functional Perspective and Implications of Gene Expression by Noncoding RNAs. Cancer Transl Med [serial online] 2015 [cited 2019 Nov 17];1:137-52. Available from: http://www.cancertm.com/text.asp?2015/1/4/137/163805


  Introduction Top


Since the development of DNA microarray to the conclusion of human genome project, it has been known that about 23,000 genes encode proteins in human. However, these numbers of genes constitute for only 2% of the genome while the vast majority of the rest are transcribed into noncoding RNAs (ncRNAs) which in turn regulate the expression of encoding genes. Based on their function and length, ncRNAs are classified into "housekeeping" ncRNAs, small ncRNAs, and long ncRNAs (lncRNAs). The "housekeeping" ncRNAs, such as small nucleolar RNAs, transfer RNAs, and ribosomal RNAs, form the critical components of cell organelles, while both of small ncRNAs and lncRNAs are well-known key regulators of gene expression. Considerable studies have demonstrated that both small ncRNAs and lncRNAs play an important role in almost all the aspects of cellular processes in physiological and pathological activities. Notably, as many ncRNAs are found regulating gene expression in order to maintain normal tissue functions, their dysfunctions are associated with a great variety of human diseases, such as cancers, neural system disorders, metabolic diseases, and defects during embryonic development. [1] Therefore, the studies on functions of these ncRNAs have not only extended our view on the regulatory network of the gene expression, but also provided the therapeutic targets for clinical application. In this review we will delineate the biological features, primary function, and mechanistic themes of two major classes of mammalian ncRNAs: lncRNAs and small ncRNAs including microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs).


  Overview of The Regulatory RNA World: History and Discovery of Noncoding Rnas Top


The first identified ncRNA was yeast alanine transfer RNA (tRNA) discovered in 1964 whose structure was established in 1965. [2] Then, small nuclear RNA, also referred to as U-RNA, was accidentally discovered in 1966. [3] The discovery of miRNA, in Caenorhabditis elegans, in 1993 provoked explosive interests in studying ncRNAs, especially miRNAs. [4] At the same time, the illustration of miRNA-mediated gene silencing resulted in the development of RNA interference (RNAi). The discovery of lncRNAs is dated back to 1990 with the cloning of imprinted gene H19 and X-inactive-specific transcript (Xist) by traditional gene mapping. [5],[6] However, at that time, they were just regarded as imprinted genes and were closely related to Wilms tumor disorders. The accomplishment of human genome sequencing in 2001 revealed that quite a lot of genome were transcribed into ncRNAs. [7] Soon after, the complement of human chromosome 21 and 22 sequencing in 2002 using DNA tilting array estimated for the first time that there might be abundant lncRNAs that are involved in regulating various physiological conditions. [8] However, as a limitation of the used method, the study lacks clearly defined genomic loci of interested genes and ultra-sensitivity, because of which these transcripts did not receive the attention they deserved, but were considered as transcriptional noise. In mid 2000s, various microarray technologies have been used to identify genome-wide transcription and surprisingly, the explosive investigations led to the discovery of large-scale of transcripts that assemble messenger RNA (mRNAs) but lack open read frames, revealing the prevalence of lncRNAs. [9] In 2006, another class of small RNAs were identified as RNA-PIWI protein complexes, by RNA immunoprecipitation (RIP), and RIP-Seq, which binds to Argonaute (AGO) family of proteins. [10] Since then, the regulatory RNAs have received increasing attention and have been widely investigated, aiding in the progress of biological technologies and development of new screening techniques. [11] Nowadays, with the rapid development of high throughput microarray and RNA sequencing, remarkable progress have been achieved in identifying the expressional profiles and characterizing biological functions of regulatory RNAs. [12] The timeline of discoveries of regulatory RNAs is shown in [Figure 1].
Figure 1. Timeline of discoveries of regulatory RNAs

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  The Biogenesis and Posttranscriptional Regulation of Small Noncoding RNAs and Long Noncoding RNAs Top


Small ncRNAs are < 200 nucleotides in length and usually bind to AGO protein family members. There are primarily two classes of endogenous small ncRNAs: miRNAs and piRNAs interacting with AGO and PIWI proteins, respectively. piRNAs showed stark difference with miRNAs which are shown in [Table 1], along with short interfering RNAs (siRNAs).
Table 1: Comparison of small noncoding RNAs


Click here to view


Biogenesis of microRNAS

The biogenesis of nascent miRNA (pri-mRNA) is a multi-step processes starting with transcription by RNA polymerase II. The genes responsible for miRNA biogenesis are mostly intergenic or intronic genes. In some cases, miRNAs could be transcribed from both strands of the same gene, producing two distinct miRNAs with different seed sequences. [13] The primary transcript is a ~ 80 nucleotide sequence containing a local stem-loop structure, similar to protein-coding genes, which is then capped with 5' 7-methyl- guanosine (m7G) and polyadenylated with a 3'- poly (A) tail. [14]

Following this, when necessary, the pri-miRNAs gets cleaved in two steps and are transformed into mature regulators. The first cleavage step is catalyzed in nucleus by a complex formed by DGCR8 and Drosha, which is a member of RNase III enzyme family, generating ~ 70 nucleotide sequence pre-miRNA with one or more hairpin structures. [15] Then the pre-miRNAs are recognized and exported into cytoplasm by nuclear-cytoplasmic transport factor Exportin-5 (XPO5). [15] Once in cytoplasm, they are cleaved by Dicer, another member of RNase III, to generate ~ 21-bp double stranded RNAs (miRNA/miRNA*). One strand of the duplex (miRNA) is loaded into the miRNA-induced silencing complex (RISC), while the other one (miRNA*) is released and degraded. The mechanism underlying the preferential selection of which strand gets incorporated into RISC is based on the 5'-terminal thermodynamic stability of the duplex. As found, the 5' terminal of miRNA containing A and U has a higher affinity (30-fold) to RISC than either C or U terminal, suggesting that the less stable 5' end gets selected by RISC. [16],[17] Additionally, a wide range of factors including RNA-binding proteins, growth factors, posttranscriptional editing, or modification are involved in regulating the biogenesis of miRNAs. For further information on the regulation of miRNAs biogenesis, researchers can refer to study done by Shen and Hung. [18]

Biogenesis of PIWI-interacting RNAs

PiRNAs are Dicer-independent single-strand ncRNAs that bind to PIWI subfamily of AGO proteins. They are found in high quantities in germline cells and play an important role in repressing the expression of transposons in germ line cells. During spermatogenesis, primordial germ cells (PGC) under do reprogramming to erase all the DNA methyl markers, which leads to activation of many genes that are normally silenced, such as transposons, and place the genome at high risk for damage. The discovery of piRNA was made in Drosophila melanogaster by the observation that the stellate protein-coding gene repeats were silenced in the testes. [19] In 2006, the piRNA-PIWI complexes were identified in mammalian GCs. [20]

Unlike miRNAs, piRNAs are 24-32 nucleotides in length and usually possess a Uridine at the 5' terminal and 2'-O-methyl modification at the 3' terminal. They are transcribed from intergenomic regions, termed as piRNA clusters, which contain transposable or repetitive elements and lack of sequence conservation. [21] The piRNA clusters range from a few kilobases to hundreds of kilobases and are usually localized within or close to heterochromatin. Based on the transcriptional direction, the mammalian piRNA clusters are classified as unidirectional and bidirectional clusters, which are transcribed into single strand and both sense and antisense strands. [22]

PIWI proteins, presenting a wide range of conservation among species, are primarily expressed in mammalian gonads, in development-dependent manner and essential for fertility. There are three members in mouse (MILI, MIWI, and MIWI2) and four in human (HILI, HIWI, HIWIL, and HIWI2). [23] In mouse, all the three PIWI proteins are required for male fertility and expressed during developmental stage. They bind to two different classes of piRNAs; prepachytene piRNAs, and pachytene piRNAs which are classified based on the clusters responsible for piRNA transcription. Prepachytene piRNAs are transcribed from clusters containing transposable elements, and are mainly expressed in the GCs of fetal and newborn mice associated with MILI and MIWI2. The pachytene piRNAs originates from nonrepetitive pachytene piRNA clusters in pachytene spermatocytes to round spermatids and are associated with MILI and MIWI. Unlike prepachytene piRNA clusters, only about 20% of the pachytene piRNA clusters are rich in transposable elements. Myeloblastosis A is found to play an important role in transcription of both pachytene piRNAs and MIWI. [24]

Although the mechanism of piRNAs biogenesis remains obscure, two major pathways have been proposed; primary, and ping-pong pathway. [25] In primary pathway, long primary piRNA precursors are mainly transcribed from pachytene clusters and are exported into cytoplasm where they are processed into shorter intermediates by GPAT2, a glycerol-3-phosphateacetyltransferase, located on the surface of mitochondria and functioning as MILI partnerin mice. [25],[26] Then the 5' end of the intermediates is processed by adding a Uridine, which is preferably recognized by MILI and MIWI, resulting in the incorporation of 5'U into the MID domains of PIWI proteins. Subsequently, the 3' trimming is performed by a presumably Mg 2+ -dependent exonuclease, generating mature-length piRNAs. After 2'- O-methylation at the 3' end, mediated by HEN1, the 3' ends of piRNAs are loaded into the Piwi Argonaut and Zwille domains within PIWIs to generate mature PIWI-piRNA complexes. Then the complexes are translocated into nucleus to silence transposon genes, and certain primary piRNAs undergo "ping-pong" cycle in cytoplasm to generate secondary piRNAs. [27]

In mouse, the "ping-pong" cycle is only present during the fetal prepachytene piRNA biogenesis, similar to the aubergine (Aub)-AGO3 "ping-pong" cycle in Drosophila. [27] These two factors (Aub and AGO) are suggested to complement each other's function as follows: aub cleaves the sense transcripts (primary piRNAs) at 10 nt from 5' end and show U bias, then the sense piRNAs recognize the complementary piRNA precursors by base pairing and load them onto AGO3, where the antisense transcripts are cleaved in a way similar to sense piRNAs, but with A bias, generating the secondary piRNAs. Notably, the secondary piRNAs are antisense transcripts and could recognize the complementary sense transcripts of piRNAs, possibly leading to initiation of another "ping-pong" cycle. Therefore, the transposon transcripts serve as precursors and are processed into secondary piRNAs by this feed forward mechanism, resulting in decrease of transposon and simultaneously increasing secondary piRNAs. Thus sometimes, the ping-pong cycle is considered as the amplification system for primary piRNAs. The key mechanism of "ping-pong" cycle is the 10-nt complementarity between the 5' ends of the U/A piRNA strands.

Collectively, the MILI-interacting prepachytene piRNAs in fetal gonocytes primarily undergo ping-pong cycle to produce secondary piRNAs which are associated with MIWI2. Subsequently, the piRNAs-MIWI2 complexes localize into the nucleus and silence the transposon; while postnatal, the pachytene piRNAs are transcribed from the intergenic regions though primary pathway and then bind to MILI and MIWI. [23]

There are many factors that are indispensable for piRNAs biogenesis, such as MOV10L1; a putative DEAD box RNA helicase responsible for maturation of piRNAs, and are essential for generation of both of prepachytene and pachytene piRNAs by functioning as a master regulator. Consistently, knock-down of MOV10L1 results in severe decrease of piRNAs. [28] Mouse vasa homolog (Mvh), another mouse helicase, is also found play an important role in piRNAs biogenesis in fetal GCs. [29] Finally, tudor domain-containing (TDRD) proteins including TDRD1, TDRKH, TDRD6-9, and TDRD12 are involved in dimethyl arginine modification and are important for spermatogenesis. [30] They are found associated with PIWI proteins and function as scaffolds for PIWI proteins and Trimmers. TDRD9 is suggested to be associated with MIWI2 and involved in DNA de novo methylation of active transposable elements. Although a number of important regulators involved in piRNA biogenesis have been identified, the precise mechanisms remain unclear. To gain more comprehensive knowledge about regulatory networks of piRNAs biogenesis, one may refer to the study done by Handler et al. [31]

Biogenesis of long noncoding RNAs

lncRNAs are a class of transcripts longer than 200 nucleotides, sharing many features with mRNAs, including those generated by polymerase II, processed with 5' capping and 3' polyadenylation. Similar to small ncRNAs, transcription of lncRNAs is spatiotemporally regulated and is development-dependent, and many well-known transcriptional factors such as cAMP response element binding, p53, Nanog, Oct4, and NF-kB are present on a number of lncRNAs transcription units. [32],[33],[34] Additionally, their transcription is regulated by epigenetic modification including DNA methylation, histone modification, and chromatin remodeling. In line with this, most of lncRNAs are located and transcribed from intergenic elements that are interlaced with protein coding genes and decorated with H3K4 and H3K36 trimethylation. [34] Despite these similarities, lncRNAs showed distinct features that are different from mRNAs, such as lack of open reading frame, lower abundance, and different subcellular location. lncRNAs show robust enrichment in nucleus and some of them form important nuclear bodies. [35] Recently, a study based on analyzing the high throughput sequencing data suggested that the majority of lncRNAs are transcribed independently. Moreover, most lncRNAs contain splice signals and are spliced into at least two different isoforms, but nearly half of them present a two exons-containing tendency. [36] Although lncRNA biogenesis is regarded similar to protein encoding genes, the details regulating their biogenesis are not well established. Some lncRNAs biogenesis require the formation of specific nuclear bodies, such as the formation of paraspeckles, necessary for nuclear-enriched abundant transcript 1 (NEAT1) processing. [35] Many paraspeckle proteins are found indispensable for the alternative 3'-processing and accumulation of NEAT1, as demonstrated by RNAi experiments. Particularly, CPSF6 and NUDT21 facilitate the canonical processing of NEAT1_1 by forming heterodimers, while HNRNPK enhance the production of NEAT1_2 by repressing the 3'-processing of NEAT1_1. Taken together, paraspeckle is necessary for alternative 3' end processing of NEAT1, however, whether this model could explain the biogenesis of other lncRNAs remains obscure.

Decay of microRNAs, PIWI-interacting RNAs and long noncoding RNAs

The exoribonucleases mediating the degradation of miRNAs have been identified as small RNA degrading nuclease family in Arabidopsis and Xrn2 in C. elegans, respectively. [37],[38] Recently, an analysis of miRNA stability in HEK293 cells, performed by miRNA array, reported that 95% of miRNAs have half-lives longer than 8 h and the human homologs of Xrn2 are found involved in degradation of miRNAs, while in an another study, the average of miRNA half-life was reported to be 119 h. [39] The controversial results obtained by these two studies might be related to the different time cause and different cell types, as miRNAs showed cell type-dependent expression. Further support for this cell-type turnover was reported in different types of neurons that partial miRNAs decreased rapidly in couple of hours whereas nearly half of them remained unchanged. [40] Specifically, knock-down of Rrp41, a core component of 3'- 5' exoribonucleases, resulted in about 50% increase in miR-382, while only an insignificant 26% increase was observed after knocking down of Xrn1 and Xrn2. Similarly, no significant difference was observed in the level of miR-378 after knocking down any of these three exoribonucleases. [41] This suggests that exoribonucleases might selectively regulate the stability of miRNAs. Other than exoribonucleases, RNA-binding proteins were also reported to regulate the stability of miRNA, by the observation that overexpression of translin, a RNA-binding protein, and stabilized miR-122. [42] Additionally, components of RISC, especially AGO2, also play a role in stability of miRNAs. The decrease of miRNAs in mouse embryonic fibroblast cells resulted from genetic deletion of AGO2 which could be rescued by restoring the protein. Additionally, the correlation between AU% and instability of miRNAs was suggested as analogous to that of mRNA degradation. Although several elements have been reported to mediate miRNA stability, the mechanism of miRNA turnover remains obscure.

Similarly, the biogenesis of piRNAs has been thoroughly investigated, although very little is known regarding their turnover. Besides mediating the 2'-O-methylation of the 3' end, Hen1 enzyme was also reported to stabilize piRNAs, as the mutation of Hen1 in zebra fish testes resulted in uridylation and adenylation, leading to significant decrease of piRNAs by 3'-5' degradation. [43]

Despite the identification of thousands of lncRNAs and rapid progress in functional investigation, little is known about the posttranscriptional regulation of lncRNAs and their stability. Recently, a genome-wide analysis has been performed to detect the stability of lncRNAs over a 32 h time course. [44] This study revealed that lncRNAs showed wide spectrum of half-lives ranging from < 30 min to > 48 h, with an average t [1]/[2] of 4.8 h which is shorter than mRNAs, which is 7.7 h, suggesting that lncRNAs are less stable than mRNAs. Gene ontology (GO) analysis revealed that the lncRNAs with same GO functions have similar stabilities, and moreover, there seemed to have a relationship between genome location and stability, as the genome location analysis showed that the intronic and promoter-associated lncRNAs were found less stable than intergenic, antisense and tail-to-tail bidirectional lncRNAs. Additionally, other factors also showed a correlation with lncRNA stability, such as cellular location and GC%. [44] It is found that nucleus-located lncRNAs displayed shorter half-lives than their cytoplasm-located counterparts, and this is consistent with the notion that genes involved in transcription and regulation of gene expression are less stable than those involved in metabolic processes. Similar to mRNAs, the lncRNAs with higher GC% were more stable, and this might be due to the capability of lncRNAs to form a second structure.

Collectively, the mechanisms underlying ncRNAs turnover is poorly understood. RNA-binding proteins might be the common mechanism that regulates ncRNAs degradation as most, if not all, of ncRNAs binds to these proteins. However, this hypothesis requires verification by identifying RNA-binding proteins that function in stabilizing these three species of ncRNAs. Additionally, although GC% was involved in both of miRNAs and lncRNAs decay, whether it is involved in piRNAs remains unclear.


  Mechanisms Underlying Noncoding RNAs Regulating Gene Expression Top


As mentioned above, the ability to represent various diseases as a potent biomarker makes ncRNAs a promising tool for clinical application. Although identifying the regulatory network of ncRNAs-regulated gene expression is challenging, the mechanistic analysis of ncRNAs function would benefit for understanding the roles of these regulatory RNAs in human development and diseases.

MicroRNAs-mediated gene silencing

RISC, the major executer of miRNA-mediated gene silencing, contains three core components: mature miRNA, AGO2, and glycine-tryptophan proteins of 182 KDa (GW182). The mature miRNAs contain a stretch of 6 nucleotides at the 5' end, spanning 2-7 nucleotides, which are the seed sequence targets to the 3'UTR of the cognate mRNAs by imperfect base pairing. AGO2, catalytic center of RISC, functions in cleaving target mRNAs, while GW182 serves as a scaffold for the assembling multi-protein complexes, such as poly (A)-binding proteins (PABP), PAN2-PAN3, and CCR4-NOT (carbon catabolite repression 4-negative on TATA-less) deadenylases complex. [45] After recognized by miRNAs, the targets are translocated to RISC, undergoing gene silencing by two mechanisms: translational repression and target decay.

Earlier studies suggested that the predominant mechanism underlying miRNAs-mediated gene silencing in animals is translation repression including both initiation block and elongation block. The mechanism underlying initiation block is impaired recognition of the m7G cap of mRNAs by translation initiation complex eIF4F, as well as unsuccessful assembling of 80s ribosome complex, thus resulting in repression of translation initiation. [46] Meijer et al. [47] further demonstrated that dissociation of eIF4A2, a critical component of eIF4F, from the target leads to failure of the translation initiation of complex binding to mRNAs. The translation elongation block stem, from the observation in C. elegans, so that lin14 and lin28-binding mRNAs remained associated with translating polysomes. [48] Similar observations were obtained by Petersen et al. [49] who proposed that elongation block might be caused by premature termination of translation and subsequent ribosome drop-off. However, Nottrott et al.[50] attributed the elongation block to the degrading nascent polypeptides. With the knowledge acquired from these studies, the detail mechanism of translation elongation block is awaited to future investigations.

Nowadays, miRNA-mediated targets decay also has been proved by a great number of studies in animals by comparing ribosome foot printing/profiling with mRNA levels. [51] Compared to translation block, the regulatory network of miRNA-mediated mRNA decay is much more detailed. The incorporation of targets into RISC first stimulates the deadenylation of mRNA mediated sequentially by the PAN2-PAN3 and the CCR4-NOT complexes, which were found orchestrated to GW182 proteins directly. [52] Then, the m7G at 5' ends of the targets is removed by DCP1-DCP2 complex. Ultimately, the mRNAs are degraded by unknown 5'- 3' exonucleases. [53]

Notably, increasing investigations have reported that in mammals the translation block and degradation of the targets might be coupled rather than independent, as suggested by two models. First model states that the translation repression is the dominant mechanism, whereas the decay of mRNAs might be its consequence. [54],[55] The other model states that the translational repression ensures while mRNA decay dominates the steady state of gene silence. [56] According to this model, translation repression occurs rapidly at the onset of the gene silencing. However, the strength during this period is low and the steady state of miRNA-mediated repression is consolidated by mRNA decay. Although it is unknown that which model is more reasonable, the link between these two models have been indicated by the interaction between PABP and GW182 proteins, which stimulates ribosome 80s complex formation and miRNA decay, respectively. [57]

Notably, in addition to negatively regulating gene expression, miRNAs are also reported to activate the same in some specific cellular circumstance by two patterns; direct activation and relief of repression. One of the example for direct activation is that miR206 could up-regulate the expression of Klf4 in proliferating epithelial cells, and the decrease of GW182 might be an essential feature of the latter pattern. [58] However, the mechanism for activation of gene expression by miRNA remains mystery.

PIWI-interacting RNAs

As mentioned earlier, piRNAs are essential for silencing transposons to preserve normal spermatogenesis and reproduction. The mechanisms underlying repression of mobilization and expression of transposable elements are well-documented in Drosophila, which suggests target degradation and epigenetic modification of the transposons, especially CpG DNA methylation in male fetal germline. [59] In mammals, transposons are primarily silenced by DNA methylation. In mouse, fetal prepachytene piRNAs PGCs are required for de novo methylation of transposons along with MIWI2's involvement. This is in line with its expression that restrict to a time window from 15 days postcoitum to 3 days postpartum. During this process, the MIWI2-WILI-prepachytene piRNAs complexes translocate into nucleus and induce CpG methylation of promotors at the transposon loci by DNA methyltransferase (DNMT). Although it is proposed that MIWI2 might act in upstreaming of DNMT3L, cooperating with DNMT3A and DNMT3B, the details on involvement of PIWI proteins in methylation remains mysterious and direct interaction between MIWI2 and DNMT has not been demonstrated. [60] Other than methylation, MIWI proteins also appears to be associated with apoptosis, as significant apoptosis was observed in mouse GCs after mutation of MIWI proteins.

Interestingly, the MIWI-pachytene piRNA complexes appear to silence the targets mostly by posttranscriptional gene silencing in cytoplasm. A recent study in elongating spermatids revealed that pachytene piRNAs could mediate degradation of mRNAs by imperfect base pairing, with the involvement of CAF1, an important component of deadenylases complex compromising CCR-4, CAF-1 and NOT. [61]

Long noncoding RNAs

How do lncRNAs recognize the specific loci of genome and what is the mechanism underlying lncRNAs interference gene expression? Several regulatory modes have been proposed including: (1) Mediating the chromatin structure by epigenetic modification. Indeed, this is the most well documented mechanism underlying lncRNA-mediated gene expression, as majority of lncRNAs are found in nucleus and particularly involved in epigenetic modification by recruiting silencing factors such as polycomb group proteins and polycomb repressive complex 2 (PRC2); [62] (2) regulate the assembly/activity of the transcriptional complex to modulate the initiation of transcription. For example, Dlx family proteins are homeobox transcription factors playing important roles in neurogenesis and forebrain development. Evf-2, a lncRNA, transcribed from Dlx-5/6 ultraconserved noncoding sequences, functions as a specific coactivator of Dlx2 to increase the activity of Dlx-5/6 enhancer; [63] (3) regulate the transport of transcription factors between cytoplasm and nucleus. NRON, a ncRNA repressor of nuclear factor of activate T cells (NFAT), is an important component of RNA-protein scaffold complex which acts by repressing gene expression by recruiting the phosphorylated NFAT in cytoplasm and inhibiting its nuclear localization. [64] Loss of NRON and another GTPase activating protein contain protein is found to increase the dephosphorylation of NFAT and translocation into nucleus, resulting in activation of target genes; (4) function as precursor of small RNAs, such as H19 and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). [65] Nuclear-retained ncRNA with a small tRNA-like domain and a short poly (A) tail like domain is found derived from lnc-MALAT1 by 3' end processing. [66] Generally, almost half of the miRNA sequences are present in extrons or introns of lncRNAs. [67] These precursor lncRNAs are unstable and are rapidly processed into small ncRNAs with 20-30 nts in length. Recently, an analysis revealed that small ncRNAs prefer to map the exons of lncRNAs, especially the 3' ends. [68]

The wide regulatory modes of gene expression by lncRNA are might be due to its abilities to: (1) Tether multiple proteins that recognize specific DNA sequence by functioning as scaffolds or adaptors. For example, HOX transcript antisense RNA (HOTAIR) can simultaneously bind to PRC2 (consist with H3K27 methylases zeste homolog 2 (EZH2), SUZ12, and EED) and lysine specific demethylase 1 (LSD1) - CoREST (a complex mediating demethylation of H3K4me2) by 5' domain and 3' domain, respectively, leading to H3K27 methylation and H3K4 demethylation. (2) Form RNA: dsDNA triplex. Apart from bridging chromatin modification complexes, lncRNAs could also sequester DNA. A study has reported that promoter-associated RNA (pRNA) which is a ncRNA, complementary to the rDNA promotor, can form triplex and recruit DNMT3B to the rDNA loci and mediate de novo methylation, revealing a new mechanism DNA methylation. [69] Recently, an unexpected role of polyadenylated lncRNAs, in regulating Staufen 1-mediated mRNA decay, is identified and the involved mechanism is imperfect base pairing between the two Alu elements located in lncRNAs and the target mRNAs. [70] This finding provides a new insight into the mechanism of lncRNA-mediated gene silencing and broadens the regulatory network of lncRNAs.


  Biological Functions of Noncoding RNAs Top


From a variety of screens and expression analyses, it is increasingly evident that changes in expression levels of many ncRNAs are correlated with developmental process and disease status. Numerous investigations have reported the pivotal roles of ncRNAs in various biological processes, including development, immunity, apoptosis, pluripotency, as well as cancer, and other diseases. We summarize the recent studies of ncRNAs in neural bioactivities, pluripotency, cancer, and diabetes, as well as lncRNA-specific imprinting.

In neural system disorders

It is reported that among human tissues, about 70% miRNAs are presented in nervous system, and moreover, many of them were specific to neurons, indicating the importance of miRNAs in neural system. [71] The overall roles of miRNAs in central neural system (CNS) have been studied by conditional deletion of dicer (Dgcr), which specifically disables the biogenesis of miRNAs. Using this method, a larger number of studies have demonstrated that dicer is essential for the normal function of CNS in both embryonic and adult mice. For example, loss of dicer during mouse embryonic development leads to smaller midbrains and failure of neural crest formation, accompanied by impaired development of dopaminergic neurons. [72] Consistently, genetic ablation of dicer, in glutamatergic neurons at E15.5, results in neonatal death caused by significant apoptosis of glutamatergic neurons. [73] In the midbrain of adult mice, loss of dicer results in progressive loss of dopaminergic neurons; while Dgcr in the forebrain of adult mice leads to neurodegeneration, which is associated with Alzheimer's syndrome. [74],[75] Additionally, the roles of dicer in specific neurocytes have been studied in wide range of neural cell types, such as Purkinje cells, spinal motor neurons, astroglial cells, Schwann cells, and oligodendrocytes. [76],[77],[78] All these studies reports that loss of dicer results in various neurological dysfunctions such as apoptosis, inability to differentiate, oxidative cascades, and inflammatory reaction suggesting that miRNAs present spatiotemporal dependent functions in different brain regions.

For neurological roles of individual miRNA, numerous investigations have been performed over the past decades, and indicated that most of them were implicated in differentiation of neural SCs (NSCs). miR-200, a multifunctional regulator, was found to promote the differentiation of ventral midbrain and hindbrain NSCs by targeting a cell-cycle regulator E2F3 and pluripotent factor Sox 2. [79] Similarly, miR-138, miR-338, and miR-219 positively regulate oligodendrocyte differentiation, and specially miR-219 being the strongest inducer. [80] However, some miRNAs are reported to inhibit the transition of progenitor cells into differentiated cells, such as miR-133b. It is found to repress the induction of adipose tissue derived SCs into neural-like cells by forming a feedback mechanism with insulin-like growth factor I. [81] The list of miRNAs involved in various neural disorders is listed in [Table 2].
Table 2: ncRNAs that are involved in neurological diseases


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Taken together, these studies suggests that miRNAs are critical for brain development by functioning as essential regulators in supporting neurons survival, development, neurite outgrowth, and dendritic spine formation highlighting the pivotal roles of miRNAs in extensive neurological processes.

Although most studies in CNS have focused on miRNAs, the research on the involvement of lncRNAs would provide promising knowledge for further understanding of its regulatory network in CNS. Expressional analysis of lncRNAs in different developmental stages during NSC differentiation revealed that they constitute an important part of network and are essential for neurogenesis and neuronal differentiation in both embryonic NSCs and adult NSCs, suggesting that lncRNAs were also involved in various activities of neural cells including NSC self renewal, synaptic transmission, and cognitive function. [95],[96] For example, the lncRNA lnc-Pnky was found to be essential in the self-renewal of NSCs, in both embryonic and postnatal brain, and its knock-down significantly increased neural differentiation. [97] AK053922, a transcript of Gli3, functions in specifying the neuronal subtypes by either activating or repressing sonic hedgehog signaling. [98] Furthermore, lncRNA HOTAIR, a well-known regulator of several HOXA genes, was found significantly changed during the differentiation of human iPSCs into neurons. [99] Additionally, primate-specific lncRNA BC200 was involved in regulating the protein synthesis in postsynaptic dendritic microdomains and maintaining the long-term synaptic plasticity. [100] Collectively, these evidences demonstrate that lncRNAs also played an important role in neural development and neural cell fate decision.

As lncRNAs are prevalent in CNS and play an important role in normal neuronal development and its functions, it is not surprising to know that they are dysregulated in neurological disease including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). A study on a large expression data of the whole genome microarrays in the AD11 mouse model at different neurodegeneration stages have identified several key lncRNAs as potent biomarkers, specifically in early (Arl16, Aph 1b, and Nudt19) and late stages (Snhg3, Txnl4, Tial, etc.) of AD. [101] Moreover, 5 lncRNAs are found common to these two stages, and one of which is Sox2 overlapping transcript, suggesting its central importance in AD. [101] HD is caused by the expansion of a CAG triplet repeats in the huntington gene, resulting in the mutation of huntington protein and aberrant nuclear-cytoplasmic trafficking of Ri-silencing transcription factor (REST)/neuron-restrictive silencer factor, which is a critical transcriptional regulator in HD. lnc-HAR1 was found significantly decreased in HD brain tissues, possibly mediated by REST as REST is known to target HAR1 locus and repress its transcription. [102] Besides AD and HD, lncRNAs are also involved in ALS as indicated by the observation that NEAT1_2 is up-regulated in ALS. Moreover, it is found directly bind to TDP-43, a major component of ubiquitinated protein aggregates, and FUS/TLS, a member of the ten-eleven translocation (TET) protein family. [103] These two proteins are frequently dysregulated in ALS patients, suggesting that NEAT1_2 may function as scaffold for RNA-binding proteins in the ALS spinal motor neurons.

In cancers

Nowadays, studies have identified substantial ncRNAs associated with tumorigenesis in almost all kinds of tissues.

The global miRNA defects caused by mutation of miRNAs-processing proteins, such as DICER1, TARBP2, and XPO5, were also found in various cancers. miR-15 and miR-16 were the firstly identified miRNAs that involved in prostate cancer by functioning as tumor repressors. [104] They were found inversely related to the level of Bcl2, which is a well-known oncogene. In pancreatic cancer cells, miR-143/145 was reported to repress the cancer progression by targeting NEDD9. Similarly, miR-145 inhibits breast cancer cell growth by targeting RTKN. [105],[106] Another well-known tumor repressor is let-7 family which is found to target various oncogenes and is involved in inhibiting genes that are responsible for cell proliferation and cell cycle pathways, such as CDC34, CDK8, and CDK6. [107] The down-regulation of let-7 was frequently found in various kinds of cancers, and the restoration of let-7 expression was found to consistently inhibit cancer progression. One possible reason might be that it could promote cancer SC differentiation. [108] Besides, cumulative evidence has suggested that miR-200 family play an essential role in inhibiting epithelial-mesenchymal transition in epithelial cancers, a critical step of cancer metastasis, as loss of miR-200 resulted in down-regulation of E-cadherin and induction of mesenchymal-like cell morphology, as well as an increase of cell motility in breast cancers. Conversely, enforced expression of miR-200 in mesenchymal cells promoted mesenchymal-epithelial transition (MET).

It is notable that many of miRNAs are selectively expressed in specific tissues or developmental stages. Bhattacharyya et al. [109] demonstrated that miRNAs carried an unique signature within breast cancers and classified several subtypes according to distinct miRNA expression profiles, highlighting the importance of miRNA in identifying biomarkers of cancers. Due to these pioneering studies, progress on the involvement of miRNAs in cancer diagnosis, subtyping, as well as the mechanism underlying drug-resistance provides great value for clinical application.

The first discovery of involvement of piRNAs-PIWIs in cancers was drastic up-regulation of HIWI in human semiformal. [110] From then on, the dysregulation of piRNAs and HIWI proteins have been found associated with wide variety of cancers including renal cell carcinoma, gastrointestinal stromal cancer, and colon cancer. [111] Moreover, over expression of HIWI in mesenchymal SCs is found to significantly increase the hypermethylation of the tumor repressor promoters, resulting in transformation of hematopoietic SCs into sarcomas. [112] Other than HIWI, up-regulation of HILI is also frequently found in tumors, possibly by promoting cell proliferation and inhibiting apoptosis which are mediated by STAT3/BCL signaling pathway. [113] Moreover, PIWI2 in Hela cells is found to repress the expression of p53 by driving the formation of nuclear PIWI2-SRC-STAT3 complex, resulting in histone modification of p53 promoter. [114] Recently, by small RNA sequencing, 8 piRNAs have been identified to be differentially expressed in human breast cancers and normal counterparts. [115]

Besides promoting tumorigenesis, some piRNAs are also involved in repressing tumor aggregation. For example, piR-823 was found to suppress tumor growth in gastric cancers, and the mechanism is probably by increasing apoptosis of tumor cells. [116] [Table 3] shows the involvement of other piRNAs in wide range of cancers.
Table 3: ncRNAs that are involved in cancers


Click here to view


lncRNAs have also been associated with cancer, as many lncRNAs are aberrantly expressed in cancers and even serve as critical triggers for malignant transformation [Table 3]. For example, lnc-prostate cancer gene 3, which is found up-regulated in prostatic cancers, has been regarded as a more specific biomarker than the commonly used prostatic specific antigen. [132] Another lncRNA, lnc-HULC, is considered as a potent diagnostic biomarker of hepatocellular carcinoma, as it is frequently detected in hepatocellular tumor tissues. [133] Similarly, several promising biomarkers for different cancers have been identified by a number of other studies, such as MALAT1 for prostatic cancer, AA174084 for gastric cancer, and certain lncRNAs including MEG3, MALAT1, HOTAIR, NEAT1, and UCA1 for oral squamous cell carcinoma. [123]

lnc-HOTAIR (HOX antisense intergenic RNA) transcribed from the intersection of HOXC locus with polyadenylation and 2.2-kb in length, functions in repressing the transcription of HOXD locus. It is found up-regulated in several kinds of cancers such as colorectal cancer, breast cancer, and hepatocellular carcinoma, and the patients with high level of HOTAIR often present with larger tumor size and poorer prognoses. Moreover, over expression of HOTAIR in these tumors, under in vitro conditions, promoted tumor cell invasiveness and metastasis. The positive relation between HOTAIR and cancer aggregation might be contributed to the interaction between HOTAIR and multiple chromatin modifiers such as PRC2, REST, coREST, and LSD1, leading to inactivation of tumor repressors by demethylating H3K4 and H3K27 trimethylation. [134],[135],[136] Recently, although HOTAIR is also reported as a negative biomarker of other cancers such as lung, pancreatic, and colon cancers, a meta-analysis revealed that it is still a reliable biomarker for digestive system malignancies. [137]

H19 is another well studied lncRNA which is transcribed from maternal allele and essential for genomic imprinting during development. Up-regulated H19 is found in various cancers, possibly resulting from loss of imprinting in paternal allele. In bladder cancer cells, increased expression of H19 promoted their migration, possibly by associating with enhancer of EZH2, leading to activation of Wnt/-catanin and degradation of E-cadherin. [128] In hepatocellular cancers, elevated H19 is found to induce the multidrug resistance 1 (MDR1)-associated drug resistance by regulating the methylation of MDR1 promotor. [138] Consistently, deletion of H19 could delay the liver tumor formation by promoting apoptosis. [139] In addition, H19 also act as an oncogenic lncRNA in Bcr-Abl chronic myeloid leukemia (CML), as down-regulation of H19 suppressed the CML cells proliferation and attenuated tumor formation.

Apart from the oncogenic lncRNAs, several lncRNAs are identified as tumor repressors, such as maternally expression gene 3 (MG3). It was found significantly down-regulated in glioma, meningioma, myeloid leukemia, and pituitary adenoma, and the potential mechanism might be attributed to its ability to facilitate the activity of p53 and inhibit cell proliferation even when p53 was absent. [140] Recently, conditional deletion of the Xist in mouse hematopoietic cells resulted in formation of hematologic cancer, suggesting that Xist might also function as a tumor repressor. [141] However, evidence for the relevance of Xist in cancer is limited and the mechanism is still obscure.

In diabetes

Diabetes mellitus is a worldwide socioeconomic health problem. It is a complex metabolic disorder associated with genetic background, environmental trigger and lifestyle factors. [142],[143] The disease is characterized with increase in blood glucose level which is due to either reduced insulin secretion from the pancreatic β cell or impaired response to the insulin at the target cells.

A series of miRNAs have been identified in mouse and human islets necessary for islet's normal development and function through processing enzyme dicer1, conditional deletion using Pdx-1 or RIP-mediated Cre recombination. [144],[145],[146] Dicer1 deletion in adult mouse β cells shows a dramatic decrease in insulin level and insulin mRNA leading to an obvious diabetic phenotype. [147] Moreover, studies indicate that individual miRNAs play a key role in multiple biological processes in β cell specification and insulin secretion. For example, miR-375 was one of the first miRNA identified in the pancreas that functions as a negative regulator of insulin secretion through its target myotrophin. [148] Deletion of miR-375 in islets results in decreased numbers of β-cells and increased numbers of α-cells ending up in hyperglycaemia. [149] This reveals the importance of miR-375 in the establishment of normal pancreatic cell mass and hormones secretion. Moreover, another miRNA, miR-7 is expressed during pancreas development and its overexpression in developing pancreas explants or in transgenic mice reduces expression levels of pancreatic transcription factor, Paired box 6, which then inhibits α- and β-cell differentiation. [150] Transgenic mice overexpressing miR-7 in β cells, impairs insulin secretion, and

#946; cell dedifferentiation and causes diabetes. [151] Importantly, genetic inactivation of miR-7 in β cells increases insulin secretion. [151] Taken together, these studies define a requirement for miRNAs in β-cell physiological and pathological development.

With over 1100 lncRNAs now identified in β cells, there is growing evidence for their involvement in diabetes. [152] Islet lncRNAs are dynamically regulated and are an integral component of the β cell differentiation and maturation program. Depletion of HI-LNC25, a β cell-specific lncRNA, downregulated GLIS3 mRNA, which is known as a susceptibility gene for Type 1 and Type 2 diabetes and modulates pancreatic β cell apoptosis. [152],[153] LncRNAs can also promote β cell function through the regulation of imprinted loci. [154] The lncRNA MEG3 can regulate the expression level of polycomb repressive complex 2 which then silences the imprinted paternal Dlk1 locus. Interestingly, reduction of MEG3 correlates with hypermethylation and misregulation of the Dlk1 locus and is found in human islets from T2D donors. [155] More importantly, genome-wide association studies (GWAS) shows that single nucleotide polymorphisms (SNPs) correlates with diabetic phenotype and lncRNAs are responsible for the effects of some of these SNPs. [152] Multiple Type 2 diabetes susceptibility loci, mapped in GWAS, shows a lead SNP inside lncRNA genes, such as KCNQ1 locus, CCND2 locus, and CDKN2A/CDKN2B locus (antisense ncRNA in the INK4 locus). [152],[156] Although some evidence had shown that lncRNAs can regulate the highly significant T2D loci, further detailed investigation of more specific lncRNAs involved in diabetes are required to be elucidated.

In pluripotency and development

The most abundant and well-known miRNA in mouse embryonic stem cells (ESCs) are miR290-295 and miR-17-92 clusters, while the predominant miRNAs of human ESCs (hESCs) are miR-371-372 cluster and miR-302-367 cluster. [157] Interestingly, further studies revealed that these clusters are dominated by a conserved family called ESC-specific cell cycle regulating miRNA family (ESCC miRNAs) possessing similar seed sequence AAGUGC. [158] Another well documented miRNA which is critical for maintaining pluripotency, is lin28. Loss-of-function analysis demonstrated that it could inhibit pri-let-7 family miRNAs, which targets hundreds of members of pluripotent regulators and is involved in differentiation. All the promotors of these clusters are largely co-occupied by the core pluripotent factors, such as Oct4, Sox2, Nanog, c-Myc, and Tcf3. [157] In turn, miRNAs could also regulate the abundance of these pluripotent factors. For example, miR-294 was found to activate the expression of c-Myc indirectly, and detailed studies in hESCs demonstrated that miRNA-302 could positively regulate Oct4 by targeting the repressor Nr2f2. [159],[160]

The mechanism underlying miRNAs-regulated pluripotency was revealed by the studies in mESCs with Dgcr8, which is specific for the processing of miRNAs. The Dgcr8/ mESCs showed normal phenotypes but prolonged cell cycle with most accumulated in G1 phase. [161] Moreover, when cultured in differentiating conditions, Dgcr8/ mESCs present impaired differentiation by absence or delayed expression of the differention genes. Consistently, the pluripotent markers are failed to be silenced during embryoid bodies formation of Dgcr8/ mESCs. [162]

Recently, both human and mouse somatic cells were successfully reprogrammed into iPSCs by miRNAs, especially the ESCC miRNAs. For instance, miR-290 and miR-106 are reported to enhance the reprogramming efficiency by 5-10 folds when co-transfected with OSK cocktails into mouse somatic cells. [163] Interestingly, these two miRNAs are found to have same targets, p21 and Tgfbr2. P21 is a critical cell cycle regulator and Tgfr2 is found associated to MET which is a critical process in reprogramming. Similar results have been observed in human adipose derived SCs reprogramming by the addition of miRNA-302 to the reprogramming cocktail. [160] Apart from MET, the combination of miRNA-302 and miRNA-372 could facilitate human fibroblasts reprogramming by altering epigenetic status. [164] Notably, three groups have successfully obtained iPSCs by using different reprogramming miRNA cocktails in which miRNA-302 remains the common factor, suggesting the central role of miRNA-302 in pluripotency. [165],[166],[167] Although the miRNAs-only iPSC reprogramming efficiency is low, homozygous and integration free generation of iPSCs has been obtained, which provides remarkable value for future clinical application.

lncRNAs are also implicated in SC self-renewal and fate decision. Recently, a study of a large-scale screening of lncRNA in mESCs was performed by combined knock-down and localization analysis of ncRNAs where3 lncRNAs, Panct 1-3, were identified to be involved in mESC pluripotency. [168] Another study on 226 lncRNAs identified 26 lncRNAs that were associated with maintenance of pluripotent state, and knock-down of the individual 26 lincRNAs induced differentiation of mESCs. [34] Similar to miRNAs, some lncRNAs also play critical roles in somatic cell reprogramming. Glt2, transcribed from Dlk1-Dio3 imprinted gene clusters and maternally expressed, is closely related to the pluripotent status of iPSCs and might serve as a marker of fully reprogrammed iPSCs. [169] Coincidently, lincRNA-RoR is demonstrated to promote reprogramming to more than 2-fold, after overexpression, while knock-down of lincRNA-RoR results in increased apoptosis induced by p53 pathway. [170] Additionally, a study in hESCs suggested that lincRNA-RoR could form a feed-back loop with the core pluripotent factors by sharing regulatory miRNA, thus protecting them from miRNA-mediated degradation. [171] These studies suggest that the pluripotent role of lincRNA-RoR is mediated by multiple pathways.

The mechanisms underlying regulation of pluripotency by lncRNAs are not fully understood. However, one of the most prevailing hypotheses is that lncRNAs act as a scaffold and recruit chromatin-modifying complexes to the target loci, thus modifying the epigenetic profile that is, closely related to the reprogramming state of iPSCs. A study demonstrated that polycomb group of proteins are involved in lncRNA silencing by mediating H3K27 methylation of the target genes. [172] Consistently, the 5' end of HOTAIR is found boundto PRC2 and 3' end bound to LSD1, which is a histone demethylase, thus mediating the methylation and demethylation of targets.

Long noncoding RNAs in X chromosome: imprinting

In 1975, the discovery that twice as manyRNAs were contained in purified chromatin as DNAs, raised the idea that RNAs may be associated with chromatin structure and gene regulation. [173] Genetic studies in the following years revealed several lncRNAs related to heterochromatin formation and gene imprinting which the parental alleles usually differentially express. Here, we focused on Xist which is one of the most well-known lncRNAs. It is transcribed from one of X chromosome in female and plays a pivotal role in another Xi, allowing for dosage compensation between male and female. After transcription, Xist spread along the whole X chromosome, resulting in the condensation and inactivation of Xi by triggering a series of chromatin changes, such as recruiting the PRC2 to induce trimethylation of H3K27 throughout the Xi. During this process, RepA, another lncRNA of 1.6-kb in length with sequences similar to the 5' region of Xist, is involved in promoting Xi by recruiting PRC2 even in the absence of Xist. [174] Recently, the mechanism underlying Xist-mediated XCI was revealed by CHART-seq. [175] According to this study, Xist spreading occurs in a stage specific manner that during de novo XCI in embryonic cells, following two-step program; initiating with targeting gene rich regions and then gene poor regions. During the maintenance of XCI in somatic cells, Xist spreads both to gene rich and gene poor regions almost simultaneously. However, the mechanism that regulates different pattern of Xist spreading in embryonic and somatic cells is unknown. Conversely, Tsix, the complementary lncRNA of Xist, serves to prevent the accumulation of Xist on the active X chromosome to maintain its active state. [176]


  The Crosstalk Between Small Noncoding Rnas and Recent Endogenous Small Interfering Rnas In animals Top


Although it seems like the three classes of ncRNAs repress specific targets and mediate gene silencing independently, it is interesting to see if there is a regulatory crosstalk between ncRNAs. Recently, an analysis on the photoactivatable ribonucleoside crossing and immunoprecipitation datasets revealed that miRNAs could potentially target lncRNAs with positional preference for the mid regions and 3' ends. [177] Another study systematically analyzed larger scale of miRNA-mediated regulatory networks by analyzing RNA-binding protein sites. About 10,000 competing endogenous RNA pairs were identified, providing comprehensive miRNA-lncRNA interaction networks. [178]

Another important finding, not fully summary sized in this review but should be noted, is the progress on the recognition and functional investigations in ncRNAs. Until recently, among animals, only nematodes had a well-defined endogenous siRNA (endo-siRNA) pathway. This has changed dramatically with the recent discovery of diverse intramolecular and intermolecular substrates that generate endo-siRNAs in D. melanogaster and mice. These findings suggest a broad and possibly conserved role of endogenous RNAi in regulating host gene expression and transposable element transcripts. They also raise many questions regarding the biogenesis and function of small regulatory RNAs in animals. [179],[180],[181]


  Future Issues Top


Overall, ncRNAs play wide and extremely important roles in regulating gene expression inmultiple ways, which makes them pivotal regulators in various biological processes. Although amazing progress on theconsiderable roles of ncRNAs has been made, a few outstanding questions remain unsolved:

  • What is the mechanism underlying the spatiotemporal expressional profile of miRNAs? Is it related to epigenetics?
  • As an individual miRNA usually targets to dozens of or even hundreds of different mRNAs, and conversely, single RNA is also cooperatively regulated by many miRNA, what is the controller behind this multi target/regulator model?
  • How PIWI proteins modulate the epigenetic status and whether PIWI-independent piRNAs are available?
  • Except in germ line cells and tumors, whether piRNAs are expressed in mammalian somatic cells, and if any, what is the target spectrum and function?
  • How lncRNAs specifically bind to the selective targets of genome?
  • What are the detailed mechanisms by which lncRNAs are generated, posttranscriptionally regulated and degraded?
  • Whether there is a crosstalk between ncRNAs, especially in human diseases?


Answers to these questions would not only shed light on the regulatory circuit of gene expression, but also will be of a remarkable value for clinical translation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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