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• W1827431288 abstract "Review29 October 2015free access Long non-coding RNAs in corticogenesis: deciphering the non-coding code of the brain Julieta Aprea DFG-Research Center and Cluster of Excellence for Regenerative Therapies, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany Search for more papers by this author Federico Calegari Corresponding Author DFG-Research Center and Cluster of Excellence for Regenerative Therapies, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany Search for more papers by this author Julieta Aprea DFG-Research Center and Cluster of Excellence for Regenerative Therapies, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany Search for more papers by this author Federico Calegari Corresponding Author DFG-Research Center and Cluster of Excellence for Regenerative Therapies, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany Search for more papers by this author Author Information Julieta Aprea1 and Federico Calegari 1 1DFG-Research Center and Cluster of Excellence for Regenerative Therapies, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany *Corresponding author. Tel: +49 351 458 82204; E-mail: [email protected] EMBO J (2015)34:2865-2884https://doi.org/10.15252/embj.201592655 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Evidence on the role of long non-coding (lnc) RNAs has been accumulating over decades, but it has been only recently that advances in sequencing technologies have allowed the field to fully appreciate their abundance and diversity. Despite this, only a handful of lncRNAs have been phenotypically or mechanistically studied. Moreover, novel lncRNAs and new classes of RNAs are being discovered at growing pace, suggesting that this class of molecules may have functions as diverse as protein-coding genes. Interestingly, the brain is the organ where lncRNAs have the most peculiar features including the highest number of lncRNAs that are expressed, proportion of tissue-specific lncRNAs and highest signals of evolutionary conservation. In this work, we critically review the current knowledge about the steps that have led to the identification of the non-coding transcriptome including the general features of lncRNAs in different contexts in terms of both their genomic organisation, evolutionary origin, patterns of expression, and function in the developing and adult mammalian brain. Glossary Cryptic promoter Promoter-like sequences located within open reading frames (ORFs) that are usually not accessible to the transcriptional machinery. Perturbations in the chromatin structure can lead to the exposure of these sequences and to aberrant transcription from inside ORFs (Smolle & Workman, 2013). Enhancer Cis-acting DNA sequence that can heighten transcription from distal promoters (even up to 1 Mb away). Enhancers interact with the corresponding promoters through DNA loops recruiting transcription factors and the transcriptional machinery. Initially identified genome wide as highly conserved non-coding DNA sequences that induce tissue-specific expression when linked to minimal promoters and currently assessed through specific chromatin modifications such as on histones and binding of a transcriptional coactivator (Zhou et al, 2011; Pennacchio et al, 2013). Homolog A gene related to a second gene by descent from a common ancestral DNA sequence caused by the event of speciation (ortholog) or genetic duplication (paralog). Ortholog Genes in different species that evolved from a common ancestral gene by speciation. Normally, orthologs retain similar functions in the course of evolution allowing reliable prediction of gene function in newly sequenced genomes. Paralog Genes related by duplication within the genome of a single species. Paralogs typically evolve new functions even if related to the original one. Promoter DNA sequence proximal to the transcription start site, usually considering the upstream 2 Kb sequence as an approximation, that integrates the regulatory input into transcription initiation. It contains sites for the binding of the transcriptional machinery, transcription factors and cofactors (Zhou et al, 2011; Lenhard et al, 2012). Transposable elements (TEs) Genomic sequences that can translocate to another location or change their copy number in the genome. Class I TEs move through a reverse-transcribed RNA intermediate and include, according to their reverse transcriptase and mechanistic features, long terminal repeats (LTR)/endogenous retroviruses (ERV) and long and short interspersed nuclear elements (LINEs and SINEs). Class II TE do not depend on an RNA intermediate and include the subclass 1, which moves through a “cut-and-paste” mechanism and subclass 2, which duplicates without double strand cleavage (Wicker et al, 2007; Rebollo et al, 2012). Introduction Proteins have long been regarded as the only molecules decoding the genetic information. Yet, plenty of genes performing this function at the RNA level have gradually been described since more than half a century (Eddy, 2001; Morris & Mattick, 2014). These non-coding RNAs carry out biological functions as diverse as proteins do, both as housekeeping and as regulatory molecules (Pauli et al, 2011), challenging proteins as executors of all genetic programmes. Housekeeping non-coding RNAs are involved in basic cellular functions and include rRNAs, tRNAs, snoRNAs and snRNAs (see Table 1 for abbreviations and functions). Regulatory non-coding RNAs are usually classified into small and long non-coding RNAs based on a threshold of 200 nucleotides. Small non-coding RNAs with sizes ranging from 18 to 32 nucleotides include, among others, miRNAs, esiRNAs and piRNAs (Table 1) that are mainly involved in transcriptional and posttranscriptional regulation of gene expression through RNA interference (Pauli et al, 2011). Long non-coding (lnc) RNAs are, in turn, defined as RNAs longer than 200 nucleotides (a threshold based on technical limitations of RNAseq library preparations) lacking coding potential as assessed by a number of bioinformatic tools (Rinn & Chang, 2012; Ilott & Ponting, 2013; Ulitsky & Bartel, 2013). Though a few examples of lncRNAs have been known and studied for decades, including Xist, H19 and Air (Rinn & Chang, 2012; Morris & Mattick, 2014), lncRNAs remain altogether among the last classes of non-coding RNAs to have been described and, to date, the least understood. Table 1. Main classes on non-coding RNAs Abbreviation Name Function and main characteristics Reviewed by Housekeeping RNAs rRNA ribosomal RNA Comprises most of the RNA in a cell and forms the core of the ribosomes, positions the tRNAs on the mRNAs and catalyzes the formation of peptide bonds Mauro & Edelman (2007), Simonovic & Steitz (2009) tRNA transfer RNA Adaptor molecules between the mRNA codons and the corresponding amino acids Ibba & Soll (2000) snoRNA small nucleolar RNA Processes and chemically modifies rRNAs in the nucleolus Matera et al (2007) snRNA small nuclear RNA Pre-mRNA splicing and other processes Matera et al (2007) scaRNAs small cajal RNAs Involved in modifying snoRNAs and snRNAs Matera et al (2007) Regulatory RNAs Small RNAs (21–31 nt) Guide the RNA-induced silencing complex (RISC) through base pairing to the corresponding targets Siomi & Siomi (2009), Hirose et al (2014) miRNA micro RNA Require the RNAse III endonuclease complexes Drosha (nuclear) and Dicer (cytoplasmatic) for their biogenesis. miRNAs can inhibit gene expression either by promoting mRNA degradation or by inhibiting translation Siomi & Siomi (2009), Hirose et al (2014) esiRNA endogenous small interfering RNA Drosha-independent, Dicer-dependent. Essential for oocyte maturation in mice Siomi & Siomi (2009), Hirose et al (2014) piRNA PIWI-interacting RNA Drosha and Dicer independent. In germ-cells, interact with the PIWI subfamily of Argounaute proteins. Involved in genome stability by suppressing transposon activity Siomi & Siomi (2009), Hirose et al (2014) Long RNAs (> 200 nt) lncRNA long noncoding RNA Multiple functions in gene expression, modulating protein activity and acting as structural RNAs Geisler & Coller (2013) circRNA circular RNA Originate from head-to-tail splicing of mRNAs. Act as miRNA sponges or regulating the splicing of its own gene. Other functions still unknown Lasda & Parker (2014) RNAs transcribed at regulatory regions eRNAs enhacer RNAs Bidirectional, relatively short and unpolyadenylated transcripts originating from enhancer elements Natoli & Andrau (2012), Lam et al (2014) PROMPTs promoter upstream transcripts Bidirectional, unstable transcripts originating upstream of promoter elements Jacquier (2009), Wei et al (2011) Main classes of housekeeping and regulatory non-coding RNAs summarising their main characteristics and functions. Transcribed regulatory regions, only two examples are shown (see references for additional examples). nt, nucleotides. In the early 2000s, several studies aiming to characterise the full coding capacity of the mammalian genome initially reported that there might be as many non-coding as coding genes (Rinn & Chang, 2012; Morris & Mattick, 2014). These studies included the FANTOM project based on full-length cDNA cloning and Sanger sequencing (Okazaki et al, 2002; Carninci et al, 2005) and other transcriptome studies based on tiling microarrays (Kapranov et al, 2002; Rinn et al, 2003). Other tools, such as chromatin state maps and RNA polymerase II occupancy, were also used to identify transcribed genomic regions (Guttman et al, 2009; De Santa et al, 2010). However, it was with the urge of massively parallel sequencing and development of RNAseq that the lncRNA component of several transcriptomes was thoroughly assessed and thousands of novel lncRNAs identified (Rinn & Chang, 2012; Ilott & Ponting, 2013; Ulitsky & Bartel, 2013). To date, lncRNAs have been studied in several organisms, tissues and cell types both during development and during adulthood, revealing thousands of lncRNAs with exquisite cell type, tissue and developmental stage specificity from which several characteristics of lncRNAs have emerged (Guttman & Rinn, 2012; Ilott & Ponting, 2013). Intriguingly, the organ where lncRNAs have the most peculiar characteristics is the brain. The brain is the organ where more lncRNAs are expressed, encompassing the highest proportion of tissue-specific lncRNAs (Derrien et al, 2012; Kaushik et al, 2013; Francescatto et al, 2014; Washietl et al, 2014). Even more, brain-specific lncRNAs present the highest signals of evolutionary conservation relative to those expressed in other tissues (Ponjavic et al, 2009; He et al, 2014). Given these characteristics, lncRNAs have been proposed to play important roles in the genetic programmes regulating brain development and function (van Leeuwen & Mikkers, 2010; Qureshi et al, 2010). In this review, we first describe the general features of lncRNAs that are more likely to be relevant to reveal their function further focusing on specific roles of a number of lncRNAs whose molecular function has been described during development and adulthood of the central nervous system (CNS). By this, we aim to point out the key findings that led to the emergence of a new field in the molecular cell biology of the mammalian brain, a field that is expected to significantly expand in the near future. General characteristics of lncRNAs At the molecular level, lncRNAs are in general similar to mRNAs. As they are transcribed by RNA polymerase II (Pol II), most lncRNAs are polyadenylated, capped and frequently spliced (Ulitsky & Bartel, 2013). Only a small fraction of lncRNAs is not polyadenylated (Ilott & Ponting, 2013), including circular RNAs (circRNAs) (Salzman et al, 2012), lncRNAs flanked by snoRNAs (Yin et al, 2012) or those with a triple helical structure at their 3′ end (Wilusz et al, 2012). Other general characteristics of vertebrate lncRNAs include a lower number of exons (2–3 on average) and shorter sequences than protein-coding genes (Ulitsky & Bartel, 2013). Chromatin modification patterns, transcriptional regulation and splicing signals seem not to differ from those of coding genes, though splicing seems to occur with less efficiency (Ulitsky & Bartel, 2013). Yet, some important differences exist between lncRNAs and mRNAs, including lower sequence conservation (Guttman et al, 2009; Ørom et al, 2010; Derrien et al, 2012) and ten times lower median expression levels (Ulitsky & Bartel, 2013). These differences have been used to argue against a functional role of lncRNAs, proposing that they are a consequence of unspecific activity of Pol II leading to lowly expressed and unstable transcripts that lack signs of sequence conservation (Wang et al, 2004; Struhl, 2007; Graur et al, 2013). However, not only do lncRNAs present clear signs of evolutionary conservation (Ponjavic et al, 2007; Chodroff et al, 2010) (further discussed below) but also their low expression levels are not necessarily a consequence of low stability nor an argument for lack of function. First, lncRNAs do not seem to be particularly unstable as a group as they present a wide range of transcript half-lives, similar to that of mRNAs (Clark et al, 2012; Tani et al, 2012). Second, low levels of expression are not necessarily reflecting homogeneous expression across tissues but could rather be a consequence of cell specificity with higher expression levels in a restricted cell population, which becomes averaged down when studying groups of cells, whole tissues or organs (Djebali et al, 2012; Ilott & Ponting, 2013). Finally, even lncRNAs with low expression levels could still be functional since some regulatory mechanisms do not require high concentration of effector molecules, as, for example, for lncRNAs acting at their site of transcription or when transcription itself is a regulatory mechanism, as we shall discuss below. From genomic organisation and expression to function Several characteristics of lncRNA loci and transcripts are indicative of their function. These characteristics include lncRNA-specific expression patterns, their genomic organisation in close proximity to protein-coding genes (developmental regulators in particular) and their overlap with enhancers and transposable elements. Expression patterns of lncRNAs Studies in a variety of cell lines and organisms, including maize, fly, zebrafish, mouse and human, have found that lncRNAs present cell, tissue and/or developmental specific expression patterns to an even higher degree than protein-coding genes (Ravasi et al, 2006; Dinger et al, 2008a; Guttman et al, 2010; Cabili et al, 2011; Ulitsky et al, 2011; Derrien et al, 2012; Djebali et al, 2012; Pauli et al, 2012; Wamstad et al, 2012; Young et al, 2012; Li et al, 2014). These specific expression patterns are reminiscent of genes with regulatory functions and have been considered as one indication of lncRNAs having roles in development and cell identity (Mercer et al, 2008; Mattick & Dinger, 2013). However, expression patterns alone are not sufficient to validate function since lncRNAs may theoretically be the result of unspecific transcription from cryptic promoters or intergenic sequences that happen to have high affinity for the transcription machinery (Khaitovich et al, 2006; Ravasi et al, 2006; Struhl, 2007; Ulitsky & Bartel, 2013). Accordingly, lncRNAs' specific expression patterns would result from cell type, tissue or developmental changes in the chromatin accessibility of the corresponding loci and/or from transcriptional regulatory activity proximal to their loci (Khaitovich et al, 2006; Ravasi et al, 2006; Struhl, 2007). Yet, it remains difficult to explain how such “transcriptional noise” would result in expression patterns even more specific than those of protein-coding genes (Guttman et al, 2010; Cabili et al, 2011; Derrien et al, 2012; Djebali et al, 2012; Pauli et al, 2012). Equally unexpected for non-functional transcripts is their tissue-specific splicing patterns (Ravasi et al, 2006; Aprea et al, 2015) and the conservation of their promoters and transcription factor-binding sites at a level comparable to those of protein-coding genes (Carninci et al, 2005; Ponjavic et al, 2007; Guttman et al, 2009; Necsulea et al, 2014) (further discussed below). This seems to imply that the specific expression patterns of lncRNAs are a consequence of a highly regulated transcriptional programme rather than “noise” and, thus, that at least a portion of them are likely involved in biological functions including regulation of key developmental programmes and cell identity (Mattick, 2011; Necsulea et al, 2014). Genomic proximity to developmental regulators Another interesting feature of lncRNAs supporting their role in development, and perhaps related to their specific expression patterns, is their preferential genomic localisation in proximity to, or overlapping, developmental regulators and transcription factors (Fig 1) (Dinger et al, 2008a; Mercer et al, 2008; Guttman et al, 2009; Ponjavic et al, 2009; Cabili et al, 2011; Ulitsky et al, 2011; Pauli et al, 2012; Wamstad et al, 2012; Young et al, 2012; Lepoivre et al, 2013). According to several studies, the expression patterns of most lncRNAs positively correlate with those of their neighbouring/overlapping coding gene (Dinger et al, 2008a; Ponjavic et al, 2009; Guttman et al, 2011; Derrien et al, 2012; Lepoivre et al, 2013; Sigova et al, 2013; Aprea et al, 2015). Consequently, it has been suggested that lncRNAs may regulate gene expression in cis, that is to control nearby genes in an allele-specific manner (Ponjavic et al, 2009; Wamstad et al, 2012). Some examples of cis-acting lncRNAs have been described, such as HOTTIP, a lncRNA transcribed from the 5′ end of the HOXA locus (Wang et al, 2011). This lncRNA binds to and targets the MLL/Tritorax complex in cis to the HOXA genes across 40 Kb that are brought together through chromosome looping. Recruiting the MLL/Tritorax complex leads to histone H3K4 trimethylation and activation of gene expression (Wang et al, 2011) (additional examples of cis-acting lncRNAs are described below). Figure 1. Possible genomic arrangements of lncRNAs with respect to their neighbouring genesDiagrams displaying different arrangements of coding (black) and neighbouring lncRNA (green) genes. Similar arrangements can be found for coding–coding and non-coding–non-coding gene pairs. Arrows indicate direction of transcription. Download figure Download PowerPoint The tight correlation in expression patterns of coding and non-coding transcripts should, however, not be taken as an evidence for a general role of non-coding RNAs in cis-regulatory functions. In fact, besides cis-regulatory activity, several possibilities can also explain the similar expression patterns of neighbouring genes. These include: (i) common regulatory sequences controlling the expression of both the coding and the non-coding gene, (ii) chromatin modifications spreading along the chromosome and affecting gene transcription within a chromosomal domain, and/or (iii) relocalisation of the genomic region to a transcriptionally active nuclear compartment such as transcription factors (Hurst et al, 2004; Katayama et al, 2005; Arnone et al, 2012; Bickmore, 2013). Moreover, several studies have found that the correlation between neighbouring coding and non-coding gene pairs is comparable to that found between coding–coding gene pairs (Cabili et al, 2011; Ulitsky et al, 2011). This is actually not surprising as mammalian genomes present an excess of gene pairs, independently of their coding capacity, located within 1 Kb of each other. These include bidirectional and overlapping antisense transcripts which constitute at least 10% (Adachi & Lieber, 2002; Takai & Jones, 2004; Trinklein et al, 2004; Engström et al, 2006; Li et al, 2006) and 25% (Katayama et al, 2005; Engström et al, 2006), respectively, of the genes in the human and mouse genome. These gene pairs, with conserved proximity and orientation in vertebrates when both orthologs exist (Trinklein et al, 2004; Chen et al, 2005; Engström et al, 2006; Li et al, 2006), tend to be coexpressed displaying positive and, to a much lower frequency, negative correlation (Trinklein et al, 2004; Chen et al, 2005; Katayama et al, 2005; Engström et al, 2006; Li et al, 2006; Arnone et al, 2012). In addition, a common and evolutionary conserved feature of eukaryotic genomes is the presence of chromosomal domains of genes with similar or coordinated expression patterns (Spellman & Rubin, 2002; Fukuoka et al, 2004; Hurst et al, 2004; Sémon & Duret, 2006; Woo et al, 2010). These domains can range from a few Kbs in yeast to 100 Kb in Drosophila and up to Mbs in mammals (Spellman & Rubin, 2002; Hurst et al, 2004). Domains even longer than 10 Mbs can be found, which are explained by the three dimensional structure of the chromosomes in the nucleus (Woo et al, 2010). Altogether, lncRNA proximity and coexpression with protein-coding genes is probably reflecting an evolutionary conserved genomic organisation with an abundance of bidirectional promoters resulting in an excess of head-to-head gene pairs and gene domains with coordinated gene expression. As several mechanisms can explain these coexpression patterns, this alone cannot be considered as evidence for gene regulation in cis. Yet, this information is still relevant to understand lncRNA function. Eukaryotic genomes are often organised in functional domains and/or gene pairs where genes involved in the same biological pathway cluster (Lee & Sonnhammer, 2003; Fukuoka et al, 2004; Li et al, 2006; Al-Shahrour et al, 2010; Arnone et al, 2012). Interestingly, a higher degree of expression correlation was observed for genes involved in the same biological pathway when they are in the same genomic domain rather than when they are further apart (Al-Shahrour et al, 2010). Thus, the expression correlation of gene pairs supports the involvement of lncRNAs in biological pathways similar to those of their neighbouring protein-coding gene independently of a cis-regulatory mechanism. One such example is HOTAIR, another lncRNA that in human regulates the expression of HOX genes, transcription factors involved in embryonic body plan and cell specification. HOTAIR is expressed from the HOXC locus in antisense to the HOXC genes, while it represses the HOXD locus on another chromosome. HOTAIR recruits the polycomb repressive complex 2 (PRC2) through direct interaction with the SUZ12 subunit leading to histone H3K27 trimethylation and gene repression of the HOXD locus (Rinn et al, 2007). Thus, this lncRNA transcribed from the HOXC locus is not involved in regulating HOXC genes in cis, but is involved in the same biological process as HOXC by controlling embryonic body plan through HOXD expression. Overlap with enhancers Another feature of lncRNA loci is their frequent overlap with enhancers and transposable elements. Active enhancers have been shown to be transcribed bidirectionally, producing short, unspliced, unpolyadenylated and unstable (exosome sensitive) eRNAs (Table 1) preceding the activation of the genes under control of the enhancer (Kim et al, 2010; Koch et al, 2011; Andersson et al, 2014; Arner et al, 2015). In addition, some enhancers are transcribed directionally into longer, spliced, polyadenylated transcripts with low coding capacity, that is lncRNAs (Koch et al, 2011; Kowalczyk et al, 2012). Simultaneously, more than half of lncRNAs expressed in blood cells were found to originate from transcription sites overlapping enhancers, with their expression correlating with that of the neighbouring protein-coding gene even more strongly than lncRNAs not overlapping enhancers (De Santa et al, 2010; Marques et al, 2013). As Pol II can be recruited by the enhancer for translocation to the promoter, it is possible that the juxtaposition of promoter and enhancer that stimulates transcription from the promoter leads to transcription from the enhancer as a by-product (Koch et al, 2011; Kowalczyk et al, 2012). Alternatively, the enhancer could be regulating both the expression of the overlapping lncRNA and that of the proximal protein-coding gene, with neither having any direct effect on the expression of its neighbour. Nonetheless, it is also possible that lncRNAs overlapping enhancers, or the act of transcription per se, are important for enhancer function. Pol II passage during enhancer transcription could lead to chromatin remodelling, changing the accessibility of the enhancer to transcription factors (De Santa et al, 2010; Koch et al, 2011). For example, transcription is necessary for histone acetylation in enhancers upstream of Ccl5 (De Santa et al, 2010). In other cases the enhancer could instead be acting through or together with the lncRNA. For example, the lncRNA Evf2 (or Dlx6os1) transcribed from the intergenic region between Dlx5 and Dlx6 overlaps one of the enhancers found in this region and regulates the binding of the transcription factor DLX2 to this enhancer (Feng et al, 2006). Even more, lncRNAs themselves can act as enhancers (Ørom et al, 2010), for example by cis-long range transcriptional activation through interaction with the mediator complex (Lai et al, 2013) or by targeting the WDR5/MLL histone methyltransferase complex in cis leading to activating chromatin modifications (Wang et al, 2011). Thus, the expression of a lncRNA that overlaps an active enhancer could provide information of its possible function as an eRNA or enhancer coregulator. Overlap with transposable elements In the case of lncRNA overlapping, containing or derived from transposable elements (TEs), the difference with protein-coding genes is striking. Whereas 5% of coding gene loci, and only 0.3% of coding sequences, are derived from TEs, the majority of human and mouse lncRNAs overlap at least one TE and more than 30% of their sequences are derived from TEs (Kelley & Rinn, 2012; Kapusta et al, 2013). This percentage could be even higher as the fraction of TE-derived sequences has been shown to be decreased after standard RNA extraction procedures, with a large fraction of non-coding RNAs associated with euchromatin being composed of TEs (Hall et al, 2014). The higher proportion of TE sequences in lncRNAs probably reflects their different sequence constrains, lacking codon or reading frame conservation constrains, thus accepting more readily TE insertions (Kapusta et al, 2013; Kapusta & Feschotte, 2014). Still, TE-derived sequences in lncRNAs are less frequent than in the whole genome (ca. 50% in human and mouse), probably indicating that structure and function of some lncRNAs could be disrupted by these insertions (Kapusta et al, 2013). Moreover, the TE composition of lncRNAs is different from genomic background as the former are enriched in long terminal repeats of endogenous retroviruses, and depleted of both long and short interspersed elements in human and mouse (Kelley & Rinn, 2012; Kapusta et al, 2013). Sequences of lncRNAs derived from TEs may play important roles by providing functional domains for protein interaction or base pairing (RNA–RNA or RNA–DNA). In particular, protein interaction domains in lncRNAs can be a direct consequence of TE insertions because these domains are already present in TEs to mediate the assembling of ribonucleoprotein complexes necessary for the TEs' lifecycle (Johnson & Guigó, 2014). These insertions can thus provide domains for interactions with proteins encoded within the TE or the genome, including transcription factors and chromatin modifiers (Johnson & Guigó, 2014). One example of a domain derived from TEs involved in RNA–protein interaction is present in Xist, a lncRNA essential for dosage compensation of the X chromosome in cis. The 5′ region of this transcript contains several tandem repeats that are likely derived from TEs (Elisaphenko et al, 2008). In particular, repeat A is derived from ERVB5, an endogenous retrovirus (Elisaphenko et al, 2008), and forms two hairpins that mediate the targeting of PRC2 to the inactive X chromosome leading to histone H3K27 trimethylation and repression of gene expression (Zhao et al, 2008). Additionally, TEs can provide DNA or RNA interaction domains to lncRNAs. As TEs exist as multiple copies in the genome and some of these copies form part of other transcripts in complementary orientation, each TE domain is likely capable of interacting with DNA or RNA sequences derived from the same family of TE (Johnson & Guigó, 2014). A lncRNA with such TE could regulate a whole family of transcripts or genomic regions. ANRIL is one such example. This lncRNA, encoded in a locus associated with coronary disease, acts in part by interacting with PRC1 and PRC2 while binding to the promoters of its targets in trans due to the interaction of the same Alu element (primate-specific short interspersed nuclear element) present in both the ANRIL transcript and the promoters of ANRIL-regulated genes (Holdt et al, 2013). Another example concerning Alu elements, in this case involved in RNA–RNA interaction, is implicated in Staufen 1 (STAU1)-mediated mRNA decay. LncRNAs containing Alu elements can base-pair with an Alu element in the 3′ UTR of a group of mRNAs targeted for degradation. This double-stranded RNA–RNA interaction recruits the STAU1 protein and triggers STAU1-mediated decay (Gong & Maquat, 2011). Even more, and as proposed by the repeat insertion domains of lncRNAs hypothesis, a combination of different functiona" @default.
• W1827431288 created "2016-06-24" @default.
• W1827431288 creator A5060007060 @default.
• W1827431288 creator A5086603462 @default.
• W1827431288 date "2015-10-29" @default.
• W1827431288 modified "2023-10-09" @default.
• W1827431288 title "Long non‐coding<scp>RNA</scp>s in corticogenesis: deciphering the non‐coding code of the brain" @default.
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