Long non-coding RNA
Long non-coding RNAs (long ncRNAs, lncRNA) are non-protein coding transcripts longer than 200 nucleotides (Perkel 2013). This somewhat arbitrary limit distinguishes long ncRNAs from small regulatory RNAs such as microRNAs (miRNAs), short interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs (Ma 2013).
- 1 Abundance of long ncRNAs
- 2 Genomic organization of long ncRNAs
- 3 Conservation of long ncRNAs
- 4 Long ncRNA functions
- 4.1 Long ncRNAs in the regulation of gene transcription
- 4.2 Long non-coding RNAs in post-transcriptional regulation
- 4.3 Long ncRNAs in epigenetic regulation
- 5 Long non-coding RNAs in aging and disease
- 6 Long intergenic non-coding RNAs (lincRNA)
- 7 See also
- 8 Notes
- 9 References
- 10 External links
Abundance of long ncRNAs
A recent study found only one-fifth of transcription across the human genome is associated with protein-coding genes (Kapranov 2007), indicating at least four times more long non-coding than coding RNA sequences. However, it is large-scale complementary DNA (cDNA) sequencing projects such as FANTOM (Functional Annotation of Mammalian cDNA) that reveal the complexity of this transcription (Carninci 2005). The FANTOM3 project identified ~35,000 non-coding transcripts from ~10,000 distinct loci that bear many signatures of mRNAs, including 5’ capping, splicing, and poly-adenylation, but have little or no open reading frame (ORF) (Carninci 2005). While the abundance of long ncRNAs was unanticipated, this number, nevertheless, represents a conservative lower estimate, since it omitted many singleton transcripts and non-polyadenylated transcripts (tiling array data shows more than 40% of transcripts are non-polyadenylated) (Cheng 2005). However, unambiguously identifying ncRNAs within these cDNA libraries is challenging, since it can be difficult to distinguish protein-coding transcripts from non-coding transcripts. It has been suggested through multiple studies that the brain and central nervous system express the greatest amount of long non-coding RNAs of any tissue type (Derrien 2012).
Genomic organization of long ncRNAs
The current landscape of the mammalian genome is described as numerous ‘foci’ of transcription that are separated by long stretches of intergenic space (Carninci 2005). While long ncRNAs are located and transcribed within the intergenic stretches, the majority are transcribed as complex, interlaced networks of overlapping sense and antisense transcripts that often includes protein-coding genes (Kapranov 2007). Genomic sequences within these transcriptional foci are often shared within a number of different coding and non-coding transcripts in the sense and antisense directions (Birney 2007) giving rise to a complex hierarchy of overlapping isoforms. For example, 3012 out of 8961 cDNAs previously annotated as truncated coding sequences within FANTOM2 were later designated as genuine ncRNA variants of protein-coding cDNAs (Carninci 2005). While the abundance and conservation of these interleaved arrangements suggest they have biological relevance, the complexity of these foci frustrates easy evaluation.
The GENCODE consortium has collated and analysed a comprehensive set of human lncRNA annotations and their genomic organisation, modifications, cellular locations and tissue expression profiles (Derrien 2012). Their analysis indicates human lncRNAs show a bias toward two-exon transcripts (Derrien 2012).
Conservation of long ncRNAs
Many small RNAs, such as microRNAs or snoRNAs, exhibit strong conservation across diverse species (Bentwich 2005). In contrast, in general long ncRNAs lack strong conservation, which is often cited as evidence of non-functionality (Brosius 2005; Struhl 2007). However, many well-described long ncRNAs, such as Air and Xist, are poorly conserved (Nesterova 2001), suggesting that ncRNAs may be subject to different selection pressures (Pang 2006). Unlike mRNAs, which have to conserve the codon usage and prevent frameshift mutations in a single long ORF, selection may conserve only short regions of long ncRNAs that are constrained by structure or sequence-specific interactions. Therefore, we may see selection act only over small regions of the long ncRNA transcript. Nevertheless, despite low conservation of long ncRNAs in general, it should be noted that many long ncRNAs still contain strongly conserved elements. For example, 19% of highly conserved phastCons elements occur in known introns, and another 32% in unannotated regions (Siepel 2005). Furthermore, a representative set of human long ncRNAs exhibit small, yet significant, reductions in substitution and insertion/deletion rates indicative of purifying selection that conserve the integrity of the transcript at the levels of sequence, promoter and splicing (Ponjavic 2007).
The poor conservation of ncRNAs may be the result of recent and rapid adaptive selection. For instance, ncRNAs may be more pliant to evolutionary pressures than protein-coding genes, as evidenced by the existence of many lineage specific ncRNAs, such as Xist or Air (Pang 2006). Indeed, those conserved regions of the human genome that are subject to recent evolutionary change relative to the chimpanzee genome occurs mainly in non-coding regions, many of which are transcribed (Pollard 2006; Pollard 2006). This includes a ncRNA, HAR1F, which has undergone rapid evolutionary change in humans and is specifically expressed in the Cajal-Retzius cells in the human neocortex (Pollard 2006). The observation that many functionally validated RNAs are evolving quickly (Pang 2006; Smith 2004), may result from these sequences having more plastic structure-function constraints, and we may expect a great deal of evolutionary innovation to occur in such sequences. This is supported by the existence of thousands of sequences in the mammalian genome that show poor conservation at the primary sequence level but have evidence of conserved RNA secondary structures (Torarinsson 2006; Torarinsson 2008).
Long ncRNA functions
Large scale sequencing of cDNA libraries and more recently transcriptomic sequencing by next generation sequencing indicate that long noncoding RNAs number in the order of tens of thousands in mammals. However, despite accumulating evidence suggesting that the majority of these are likely to be functional (Mercer 2009; Dinger 2009), only a relatively small proportion has been demonstrated to be biologically relevant. As of June 2014, 197 LncRNAs have been functionally annotated in LncRNAdb (a database of literature described LncRNAs) (Amral 2011), thereby, the majority (118 genes) were described in human. A further large scale sequencing study provides evidence that many transcripts thought to be LncRNAs may, in fact, be translated into proteins.
Long ncRNAs in the regulation of gene transcription
Long ncRNAs in gene-specific transcription
In eukaryotes, RNA transcription is a tightly regulated process. NcRNAs can target different aspects of this process, targeting transcriptional activators or repressors, different components of the transcription reaction including RNA polymerase (RNAP) II and even the DNA duplex to regulate gene transcription and expression (Goodrich 2006). In combination these ncRNAs may comprise a regulatory network that, including transcription factors, finely control gene expression in complex eukaryotes.
NcRNAs modulate the function of transcription factors by several different mechanisms, including functioning themselves as co-regulators, modifying transcription factor activity, or regulating the association and activity of co-regulators. For example, the ncRNA Evf-2 functions as a co-activator for the homeobox transcription factor Dlx2, which plays important roles in forebrain development and neurogenesis (Feng 2006; Panganiban 2002). Sonic hedgehog induces transcription of Evf-2 from an ultra-conserved element located between the Dlx5 and Dlx6 genes during forebrain development (Feng 2006). Evf-2 then recruits the Dlx2 transcription factor to the same ultra-conserved element whereby Dlx2 subsequently induces expression of Dlx5. The existence of other similar ultra- or highly conserved elements within the mammalian genome that are both transcribed and fulfil enhancer functions suggest Evf-2 may be illustrative of a generalised mechanism that tightly regulates important developmental genes with complex expression patterns during vertebrate growth (Pennacchio 2006; Visel 2008). Indeed, the transcription and expression of similar non-coding ultraconserved elements was recently shown to be abnormal in human leukaemia and to contribute to apoptosis in colon cancer cells, suggesting their involvement in tumorogenesis (Calin 2007).
Local ncRNAs can also recruit transcriptional programmes to regulate adjacent protein-coding gene expression. The RNA binding protein TLS, binds and inhibits the CREB binding protein and p300 histone acetyltransferease activities on a repressed gene target, cyclin D1. The recruitment of TLS to the promoter of cyclin D1 is directed by long ncRNAs expressed at low levels and tethered to 5’ regulatory regions in response to DNA damage signals (Wang 2008). Moreover, these local ncRNAs act cooperatively as ligands to modulate the activities of TLS. In the broad sense, this mechanism allows the cell to harness RNA-binding proteins, which make up one of the largest classes within the mammalian proteome, and integrate their function in transcriptional programs. A recent study found that a lncRNA in the antisense direction of the Apolipoprotein A1 (APOA1) regulates the transcription of APOA1 through epigenetic modifications.
Recent evidence has raised the possibility that transcription of genes that escape from X-inactivation might be mediated by expression of long non-coding RNA within the escaping chromosomal domains (Reinius 2010).
Long ncRNAs regulating basal transcription machinery
NcRNAs also target general transcription factors required for the RNAP II transcription of all genes (Goodrich 2006). These general factors include components of the initiation complex that assemble on promoters or involved in transcription elongation. A ncRNA transcribed from an upstream minor promoter of the dihydrofolate reductase (DHFR) gene forms a stable RNA-DNA triplex within the major promoter of DHFR to prevent the binding of the transcriptional co-factor TFIIB (Martianov 2007). This novel mechanism of regulating gene expression may in fact represent a widespread method of controlling promoter usage given that thousands of such triplexes exist in eukaryotic chromosome (Lee 1987). The U1 ncRNA can induce transcription initiation by specifically binding to and stimulating TFIIH to phosphorylate the C-terminal domain of RNAP II (Kwek 2002). In contrast the ncRNA 7SK, is able to repress transcription elongation by, in combination with HEXIM1/2, forming an inactive complex that prevents the PTEFb general transcription factor from phosphorylating the C-terminal domain of RNAP II (Kwek 2002; Yang 2001; Yik 2003), thereby repressing global elongation under stressful conditions. These examples, which bypass specific modes of regulation at individual promoters to mediate changes directly at the level of initiation and elongation transcriptional machinery, provide a means of quickly affecting global changes in gene expression.
The ability to quickly mediate global changes is also apparent in the rapid expression of non-coding repetitive sequences. The short interspersed nuclear (SINE) Alu elements in humans and analogous B1 and B2 elements in mice have succeeded in becoming the most abundant mobile elements within the genomes, comprising ~10% of the human and ~6% of the mouse genome, respectively (Lander 2001; Waterston 2002). These elements are transcribed as ncRNAs by RNAP III in response to environmental stresses such as heat shock (Liu 1995), where they then bind to RNAP II with high affinity and prevent the formation of active pre-initiation complexes (Allen 2004; Espinoza 2004; Espinoza 2007; Mariner & Walters 2008). This allows for the broad and rapid repression of gene expression in response to stress (Allen 2004; Mariner & Walters 2008).
A dissection of the functional sequences within Alu RNA transcripts has drafted a modular structure analogous to the organization of domains in protein transcription factors (Shamovsky 2008). The Alu RNA contains two ‘arms’, each of which may bind one RNAP II molecule, as well as two regulatory domains that are responsible for RNAP II transcriptional repression in vitro (Mariner 2008). These two loosely-structured domains may even be concatenated to other ncRNAs such as B1 elements to impart their repressive role (Mariner & Walters 2008). The abundance and distribution of Alu elements and similar repetitive elements throughout the mammalian genome may be partly due to these functional domains being co-opted into other long ncRNAs during evolution, with the presence of functional repeat sequence domains being a common characteristic of several known long ncRNAs including Kcnq1ot1, Xlsirt and Xist (Mattick 2003; Mohammad 2008; Wutz 2002; Zearfoss 2003).
In addition to heat shock, the expression of SINE elements (including Alu, B1, and B2 RNAs) increases during cellular stress such as viral infection (Singh 1985) in some cancer cells (Tang 2005) where they may similarly regulate global changes to gene expression. The ability of Alu and B2 RNA to bind directly to RNAP II provides a broad mechanism to repress transcription (Espinoza 2004; Mariner & Walters 2008). Nevertheless, there are specific exceptions to this global response where Alu or B2 RNAs are not found at activated promoters of genes undergoing induction, such as the heat shock genes (Mariner & Walters 2008). This additional hierarchy of regulation that exempts individual genes from the generalised repression also involves a long ncRNA, heat shock RNA-1 (HSR-1). It was argued that HSR-1 is present in mammalian cells in an inactive state, but upon stress is activated to induce the expression of heat shock genes (Shamovsky 2006). The authors found that this activation involves a conformational alteration to the structure of HSR-1 in response to rising temperatures, thereby permitting its interaction with the transcriptional activator HSF-1 that subsequently undergoes trimerisation and induces the expression of heat shock genes (Shamovsky 2006). In the broad sense, these examples illustrate a regulatory circuit nested witin ncRNAs whereby Alu or B2 RNAs repress general gene expression, while other ncRNAs activate the expression of specific genes.
Long ncRNA transcribed by RNA polymerase III
Many of the ncRNAs that interact with general transcription factors or RNAP II itself (including 7SK, Alu and B1 and B2 RNAs) are transcribed by RNAP III (Dieci 2007), thereby uncoupling the expression of these ncRNAs from the RNAP II transcriptional reaction they regulate. RNAP III also transcribes a number of additional novel ncRNAs, such as BC2, BC200 and some microRNAs and snoRNAs, in addition to the highly expressed infrastructural ‘housekeeping’ ncRNA genes such as tRNAs, 5S rRNAs and snRNAs (Dieci 2007). The existence of an RNAP III-dependent ncRNA transcriptome that regulates its RNAP II-dependent counterpart was supported by a recent study that described a novel set of ncRNAs transcribed by RNAP III with sequence homology to protein-coding genes. This prompted the authors to posit a ‘cogene/gene’ functional regulatory network (Pagano 2007), showing that one of these ncRNAs, 21A, regulates the expression its antisense partner gene, CENP-F in trans.
Long non-coding RNAs in post-transcriptional regulation
In addition to regulating transcription, ncRNAs also control various aspects of post-transcriptional mRNA processing. Similar to small regulatory RNAs such as microRNAs and snoRNAs, these functions often involve complementary base pairing with the target mRNA. The formation of RNA duplexes between complementary ncRNA and mRNA may mask key elements within the mRNA required to bind trans-acting factors, potentially effecting any step in post-transcriptional gene expression including pre-mRNA processing and splicing, transport, translation, and degradation.
Long ncRNAs in splicing
The splicing of mRNA can induce its translation and functionally diversify the repertoire of proteins it encodes. The Zeb2 mRNA, which has a particularly long 5’UTR, requires the retention of a 5’UTR intron that contains an internal ribosome entry site for efficient translation (Beltran 2008). However, retention of the intron is dependent on the expression of an antisense transcript that complements the intronic 5’ splice site (Beltran 2008). Therefore, the ectopic expression of the antisense transcript represses splicing and induces translation of the Zeb2 mRNA during mesenchymal development. Likewise, the expression of an overlapping antisense Rev-ErbAα2 transcript controls the alternative splicing of the thyroid hormone receptor ErbAα2 mRNA to form two antagonistic isoforms (Munroe 1991).
Long ncRNAs in translation
NcRNA may also apply additional regulatory pressures during translation, a property particularly exploited in neurons where the dendritic or axonal translation of mRNA in response to synaptic activity contributes to changes in synaptic plasticity and the remodelling of neuronal networks. The RNAP III transcribed BC1 and BC200 ncRNAs, that previously derived from tRNAs, are expressed in the mouse and human central nervous system, respectively (Tiedge 1993; Tiedge 1991). BC1 expression is induced in response to synaptic activity and synaptogenesis and is specifically targeted to dendrites in neurons (Muslimov 1998). Sequence complementarity between BC1 and regions of various neuron-specific mRNAs also suggest a role for BC1 in targeted translational repression (Wang 2005). Indeed it was recently shown that BC1 is associated with translational repression in dendrites to control the efficiency of dopamine D2 receptor-mediated transmission in the striatum (Centonze 2007) and BC1 RNA-deleted mice exhibit behavioural changes with reduced exploration and increased anxiety (Lewejohann 2004).
Long ncRNAs in siRNA-directed gene regulation
In addition to masking key elements within single-stranded RNA, the formation of double-stranded RNA duplexes can also provide a substrate for the generation of endogenous siRNAs (endo-siRNAs) in Drosophila and mouse oocytes (Golden 2008). The annealing of complementary sequences, such as antisense or repetitive regions between transcripts, forms an RNA duplex that may be processed by Dicer-2 into endo-siRNAs. Also, long ncRNAs that form extended intramolecular hairpins may be processed into siRNAs, compellingly illustrated by the esi-1 and esi-2 transcripts (Czech 2008). Endo-siRNAs generated from these transcripts seem particularly useful in suppressing the spread of mobile transposon elements within the genome in the germline. However, the generation of endo-siRNAs from antisense transcripts or pseudogenes may also silence the expression of their functional counterparts via RISC effector complexes, acting as an important node that integrates various modes of long and short RNA regulation, as exemplified by the Xist and Tsix (see above) (Ogawa 2008).
Long ncRNAs in epigenetic regulation
Epigenetic modifications, including histone and DNA methylation, histone acetylation and sumoylation, affect many aspects of chromosomal biology, primarily including regulation of large numbers of genes by remodeling broad chromatin domains (Kiefer 2007; Mikkelsen 2007). While it has been known for some time that RNA is an integral component of chromatin (Nickerson 1989; Rodriguez-Campos 2007), it is only recently that we are beginning to appreciate the means by which RNA is involved in pathways of chromatin modification (Chen 2008; Rinn 2007; Sanchez-Elsner 2006).
In Drosophila, long ncRNAs induce the expression of the homeotic gene, Ubx, by recruiting and directing the chromatin modifying functions of the trithorax protein Ash1 to Hox regulatory elements (Sanchez-Elsner 2006). Similar models have been proposed in mammals, where strong epigenetic mechanisms are thought to underlie the embryonic expression profiles of the Hox genes that persist throughout human development (Mazo 2007; Rinn 2007). Indeed, the human Hox genes are associated with hundreds of ncRNAs that are sequentially expressed along both the spatial and temporal axes of human development and define chromatin domains of differential histone methylation and RNA polymerase accessibility (Rinn 2007). One ncRNA, termed HOTAIR, that originates from the HOXC locus represses transcription across 40 kb of the HOXD locus by altering chromatin trimethylation state. HOTAIR is thought to achieve this by directing the action of Polycomb chromatin remodeling complexes in trans to govern the cells' epigenetic state and subsequent gene expression. Components of the Polycomb complex, including Suz12, EZH2 and EED, contain RNA binding domains that may potentially bind HOTAIR and probably other similar ncRNAs (Denisenko 1998; Katayama 2005). This example nicely illustrates a broader theme whereby ncRNAs recruit the function of a generic suite of chromatin modifying proteins to specific genomic loci, underscoring the complexity of recently published genomic maps (Mikkelsen 2007). Indeed the prevalence of long ncRNAs associated with protein coding genes may contribute to localised patterns of chromatin modifications that regulate gene expression during development. For example, the majority of protein-coding genes have antisense partners, including many tumour suppressor genes that are frequently silenced by epigenetic mechanisms in cancer (Yu 2008). A recent study observed an inverse expression profile of the p15 gene and an antisense ncRNA in leukaemia (Yu 2008). A detailed analysis showed the p15 antisense ncRNA (CDKN2BAS) was able to induce changes to heterochromatin and DNA methylation status of p15 by an unknown mechanism, thereby regulating p15 expression (Yu 2008). Therefore misexpression of the associated antisense ncRNAs may subsequently silence the tumour suppressor gene contributing towards oncogenesis.
Many emergent themes of ncRNA-directed chromatin modification were first apparent within the phenomenon of imprinting, whereby only one allele of a gene is expressed from either the maternal or the paternal chromosome. In general, imprinted genes are clustered together on chromosomes, suggesting the imprinting mechanism acts upon local chromosome domains rather than individual genes. These clusters are also often associated with long ncRNAs whose expression is correlated with the repression of the linked protein-coding gene on the same allele (Pauler 2007). Indeed, detailed analysis has revealed a crucial role for the ncRNAs Kcnqot1 and Igf2r/Air in directing imprinting (Braidotti 2004).
Almost all the genes at the Kcnq1 loci are maternally inherited, except the paternally expressed antisense ncRNA Kcnqot1 (Mitsuya 1999). Transgenic mice with truncated Kcnq1ot fail to silence the adjacent genes, suggesting that Kcnqot1 is crucial to the imprinting of genes on the paternal chromosome (Mancini-Dinardo 2006). It appears that Kcnqot1 is able to direct the trimethylation of lysine 9 (H3K9me3) and 27 of histone 3 (H3K27me3) to an imprinting centre that overlaps the Kcnqot1 promoter and actually resides within a Kcnq1 sense exon (Umlauf 2004). Similar to HOTAIR (see above), Eed-Ezh2 Polycomb complexes are recruited to the Kcnq1 loci paternal chromosome, possibly by Kcnqot1, where they may mediate gene silencing through repressive histone methylation (Umlauf 2004). A differentially methylated imprinting centre also overlaps the promoter of a long antisense ncRNA Air that is responsible for the silencing of neighbouring genes at the Igf2r locus on the paternal chromosome (Sleutels 2002; Zwart 2001). The presence of allele-specific histone methylation at the Igf2r locus suggests Air also mediates silencing via chromatin modification (Fournier 2002).
Xist and X-chromosome inactivation
The inactivation of a X-chromosome in female placental mammals is directed by one of the earliest and best characterized long ncRNAs, Xist (Wutz 2007). The expression of Xist from the future inactive X-chromosome, and its subsequent coating of the inactive X-chromosome, occurs during early embryonic stem cell differentiation. Xist expression is followed by irreversible layers of chromatin modifications that include the loss of the histone (H3K9) acetylation and H3K4 methylation that are associated with active chromatin, and the induction of repressive chromatin modifications including H4 hypoacetylation, H3K27 trimethylation (Wutz 2007), H3K9 hypermethylation and H4K20 monomethylation as well as H2AK119 monoubiquitylation. These modifications coincide with the transcriptional silencing of the X-linked genes (Morey 2004). Xist RNA also localises the histone variant macroH2A to the inactive X–chromosome (Costanzi 1998). There are additional ncRNAs that are also present at the Xist loci, including an antisense transcript Tsix, which is expressed from the future active chromosome and able to repress Xist expression by the generation of endogenous siRNA (Ogawa 2008). Together these ncRNAs ensure that only one X-chromosome is active in female mammals.
Telomeric non-coding RNAs
Telomeres form the terminal region of mammalian chromosomes and are essential for stability and aging and play central roles in diseases such as cancer (Blasco 2007). Telomeres have been long considered transcriptionally inert DNA-protein complexes until it was recently shown that telomeric repeats may be transcribed as telomeric RNAs (TelRNAs) (Schoeftner 2008) or telomeric repeat-containing RNAs (Azzalin 2007). These ncRNAs are heterogeneous in length, transcribed from several sub-telomeric loci and physically localise to telomeres. Their association with chromatin, which suggests an involvement in regulating telomere specific heterochromatin modifications, is repressed by SMG proteins that protect chromosome ends from telomere loss (Azzalin 2007). In addition, TelRNAs block telomerase activity in vitro and may therefore regulate telomerase activity (Schoeftner 2008). Although early, these studies suggest an involvement for telomeric ncRNAs in various aspects of telomere biology.
Long non-coding RNAs in aging and disease
Recent recognition that long ncRNAs function in various aspects of cell biology has focused increasing attention on their potential to contribute towards disease etiology. A handful of studies have implicated long ncRNAs in a variety of disease states and support an involvement and co-operation in neurological disease and oncogenesis.
The first published report of an alteration in lncRNA abundance in aging and human neurological disease was provided by Lukiw et al., (1992) (Lukiw et al., 1992)  in a study using short post-mortem interval Alzheimer's disease and non-Alzheimer's dementia (NAD) tissues; this early work was based on the prior identification of a primate brain-specific cytoplasmic transcript of the Alu repeat family by Watson and Sutcliffe in 1987 known as BC200 (brain, cytoplasmic, 200 nucleotide) (Watson and Sutcliffe, 1987) 
While many association studies have identified long ncRNAs that are aberrantly expressed in disease states, we have little understanding of their contribution within disease etiology. Expression analyses that compare tumor cells and normal cells have revealed changes in the expression of ncRNAs in several forms of cancer. For example, in prostate tumours, one of two overexpressed ncRNAs, PCGEM1, is correlated with increased proliferation and colony formation suggesting an involvement in regulating cell growth (Fu 2006). MALAT1 (also known as NEAT2) was originally identified as an abundantly expressed ncRNA that is upregulated during metastasis of early-stage non-small cell lung cancer and its overexpression is an early prognostic marker for poor patient survival rates (Fu 2006). More recently, the highly conserved mouse homologue of MALAT1 was found to be highly expressed in hepatocellular carcinoma (Lin 2007). Intronic antisense ncRNAs with expression correlated to the degree of tumor differentiation in prostate cancer samples have also been reported (Reis 2004). Despite a number of long ncRNAs having aberrant expression in cancer, their function and potential role in tumourogenesis is relatively unknown. For example, the ncRNAs HIS-1 and BIC have been implicated in oncogenesis and growth control, but their function in normal cells is unknown (Eis 2005; Li 1997). In addition to cancer, ncRNAs also exhibit aberrant expression in other disease states. Overexpression of PRINS is associated with psoriasis susceptibility, with PRINS expression being elevated in the uninvolved epidermis of psoriatic patients compared with both psoriatic lesions and healthy epidermis (Sonkoly 2005).
Genome-wide profiling revealed that many transcribed non-coding ultraconserved regions exhibit distinct profiles in various human cancer states (Calin 2007). An analysis of chronic lymphocytic leukaemia, colorectal carcinoma and hepatocellular carcinoma found that all three cancers exhibited aberrant expression profiles for ultraconserved ncRNAs relative to normal cells. Further analysis of one ultraconserved ncRNA suggested it behaved like an oncogene by mitigating apoptosis and subsequently expanding the number of malignant cells in colorectal cancers (Calin 2007). Many of these transcribed ultraconserved sites that exhibit distinct signatures in cancer are found at fragile sites and genomic regions associated with cancer. It seems likely that the aberrant expression of these ultraconserved ncRNAs within malignant processes results from important functions they fulfil in normal human development.
Recently, a number of association studies examining single nucleotide polymorphisms (SNPs) associated with disease states have been mapped to long ncRNAs. For example, SNPs that identified a susceptibility locus for myocardial infarction mapped to a long ncRNA, MIAT (myocardial infarction associated transcript) (Ishii 2006). Likewise, genome-wide association studies identified a region associated with coronary artery disease (McPherson 2007) that encompassed a long ncRNA, ANRIL (Pasmant 2007). ANRIL is expressed in tissues and cell types affected by atherosclerosis (Broadbend 2008, Jarinova 2009) and its altered expression is associated with a high-risk haplotype for coronary artery disease (Jarinova 2009, Liu 2009)
The complexity of the transcriptome, and our evolving understanding of its structure may inform a reinterpretation of the functional basis for many natural polymorphisms associated with disease states. Many SNPs associated with certain disease conditions are found within non-coding regions and the complex networks of non-coding transcription within these regions make it particularly difficult to elucidate the functional effects of polymorphisms. For example, a SNP both within the truncated form of ZFAT and the promoter of an antisense transcript increases the expression of ZFAT not through increasing the mRNA stability, but rather by repressing the expression of the antisense transcript (Shirasawa 2004).
The ability of long ncRNAs to regulate associated protein-coding genes may contribute to disease if misexpression of a long ncRNA deregulates a protein coding gene with clinical significance. In similar manner, an antisense long ncRNA that regulates the expression of the sense BACE1 gene, a crucial enzyme in Alzheimer’s disease etiology, exhibits elevated expression in several regions of the brain in individuals with Alzheimer's disease (Faghihi 2008). Alteration of the expression of ncRNAs may also mediate changes at an epigenetic level to affect gene expression and contribute to disease aetiology. For example, the induction of an antisense transcript by a genetic mutation led to DNA methylation and silencing of sense genes, causing β-thalassemia in a patient (Tufarelli 2003).
Long intergenic non-coding RNAs (lincRNA)
|This section requires expansion with: more examples and references. (December 2011)|
"Intergenic" refers to long non-coding RNAs that are transcribed from non-coding DNA sequences between protein-coding genes (Hesman Saey 2011; Rinn Lab lincRNA homepage). A 2013 study identified tens of thousands of human lincRNAs. Some lincRNAs attach to messenger RNA to block protein production. At least 26 different lincRNAs are needed to prevent an embryonic stem cell from differentiating. Additionally, it was proposed to classify intergenic RNA domains of at least 50 kb in length as "very long intergenic non-coding" (vlincRNAs) regions (Laurent 2010).
- Smith, JE; Alvarez-Dominguez, JR; Kline, N; Huynh, NJ; Geisler, S; Hu, W; Coller, J; Baker, KE (Jun 26, 2014). "Translation of Small Open Reading Frames within Unannotated RNA Transcripts in Saccharomyces cerevisiae.". Cell reports 7 (6): 1858–66. doi:10.1016/j.celrep.2014.05.023. PMID 24931603.
- Halley, Paul; Kadakkuzha, Beena (2014). "Regulation of the apolipoprotein gene cluster by a long noncoding RNA.". Cell Reports 6 (1): 222–30. doi:10.1016/j.celrep.2013.12.015. PMID 24388749.
- Lukiw WJ, Handley P, Wong L, Crapper McLachlan DR (Jun 1992). "BC200 RNA in normal human neocortex, non-Alzheimer dementia (NAD), and senile dementia of the Alzheimer type (AD)". Neurochem Res. 17 (6): 591–7. PMID 1603265.
- Watson JB, Sutcliffe JG (Sep 1987). "Primate brain-specific cytoplasmic transcript of the Alu repeat family". Mol Cell Biol 7 (9): 3324–7. PMID 2444875.
- Hangauer, Matthew J.; Vaughn, Ian W.; McManus, Michael T.; Rinn, John L. (20 June 2013). "Pervasive Transcription of the Human Genome Produces Thousands of Previously Unidentified Long Intergenic Noncoding RNAs". PLoS Genetics 9 (6): e1003569. doi:10.1371/journal.pgen.1003569.
- Allen E, Xie Z, Gustafson AM, Sung GH, Spatafora JW, Carrington JC (December 2004). "Evolution of microRNA genes by inverted duplication of target gene sequences in Arabidopsis thaliana". Nature Genetics 36 (12): 1282–90. doi:10.1038/ng1478. PMID 15565108.
- Amaral, P. P.; Clark, M. B.; Gascoigne, D. K.; Dinger, M. E.; Mattick, J. S. (2010). "LncRNAdb: A reference database for long noncoding RNAs". Nucleic Acids Research 39 (Database issue): D146–D151. doi:10.1093/nar/gkq1138. PMC 3013714. PMID 21112873.
- Azzalin CM, Reichenbach P, Khoriauli L, Giulotto E, Lingner J (November 2007). "Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends". Science 318 (5851): 798–801. Bibcode:2007Sci...318..798A. doi:10.1126/science.1147182. PMID 17916692.
- Beltran M, Puig I, Peña C et al. (March 2008). "A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition". Genes & Development 22 (6): 756–69. doi:10.1101/gad.455708. PMC 2275429. PMID 18347095.
- Bentwich I, Avniel A, Karov Y et al. (July 2005). "Identification of hundreds of conserved and nonconserved human microRNAs". Nature Genetics 37 (7): 766–70. doi:10.1038/ng1590. PMID 15965474.
- Birney E, Stamatoyannopoulos JA, Dutta A et al. (June 2007). "Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project". Nature 447 (7146): 799–816. Bibcode:2007Natur.447..799B. doi:10.1038/nature05874. PMC 2212820. PMID 17571346.
- Blasco MA (October 2007). "Telomere length, stem cells and aging". Nature Chemical Biology 3 (10): 640–9. doi:10.1038/nchembio.2007.38. PMID 17876321.
- Braidotti G, Baubec T, Pauler F et al. (2004). "The Air noncoding RNA: an imprinted cis-silencing transcript". Cold Spring Harbor Symposia on Quantitative Biology 69: 55–66. doi:10.1101/sqb.2004.69.55. PMC 2847179. PMID 16117633.
- Broadbent HM, Peden JF, Lorkowski S et al. (2008). "Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p". Human Molecular Genetics 17 (6): 806–14. doi:10.1093/hmg/ddm352. PMID 18048406.
- Brosius J (May 2005). "Waste not, want not--transcript excess in multicellular eukaryotes". Trends in Genetics 21 (5): 287–8. doi:10.1016/j.tig.2005.02.014. PMID 15851065.
- Calin GA, Liu CG, Ferracin M et al. (September 2007). "Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas". Cancer Cell 12 (3): 215–29. doi:10.1016/j.ccr.2007.07.027. PMID 17785203.
- Carninci P, Kasukawa T, Katayama S et al. (September 2005). "The transcriptional landscape of the mammalian genome". Science 309 (5740): 1559–63. Bibcode:2005Sci...309.1559F. doi:10.1126/science.1112014. PMID 16141072.
- Centonze D, Rossi S, Napoli I et al. (August 2007). "The brain cytoplasmic RNA BC1 regulates dopamine D2 receptor-mediated transmission in the striatum". The Journal of Neuroscience 27 (33): 8885–92. doi:10.1523/JNEUROSCI.0548-07.2007. PMID 17699670.
- Chen X, Xu H, Yuan P et al. (June 2008). "Integration of external signaling pathways with the core transcriptional network in embryonic stem cells". Cell 133 (6): 1106–17. doi:10.1016/j.cell.2008.04.043. PMID 18555785.
- Cheng J, Kapranov P, Drenkow J et al. (May 2005). "Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution". Science 308 (5725): 1149–54. Bibcode:2005Sci...308.1149C. doi:10.1126/science.1108625. PMID 15790807.
- Costanzi C, Pehrson JR (June 1998). "Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals". Nature 393 (6685): 599–601. Bibcode:1998Natur.393..599C. doi:10.1038/31275. PMID 9634239.
- Czech B, Malone CD, Zhou R et al. (June 2008). "An endogenous small interfering RNA pathway in Drosophila". Nature 453 (7196): 798–802. Bibcode:2008Natur.453..798C. doi:10.1038/nature07007. PMC 2895258. PMID 18463631.
- Denisenko O, Shnyreva M, Suzuki H, Bomsztyk K (1 October 1998). "Point mutations in the WD40 domain of Eed block its interaction with Ezh2". Molecular and Cellular Biology 18 (10): 5634–42. PMC 109149. PMID 9742080.
- Derrien, T.; Johnson, R.; Bussotti, G.; Tanzer, A.; Djebali, S.; Tilgner, H.; Guernec, G.; Martin, D.; Merkel, A.; Knowles, D. G.; Lagarde, J.; Veeravalli, L.; Ruan, X.; Ruan, Y.; Lassmann, T.; Carninci, P.; Brown, J. B.; Lipovich, L.; Gonzalez, J. M.; Thomas, M.; Davis, C. A.; Shiekhattar, R.; Gingeras, T. R.; Hubbard, T. J.; Notredame, C.; Harrow, J.; Guigó, R. (2012). "The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression". Genome Research 22 (9): 1775–1789. doi:10.1101/gr.132159.111. PMC 3431493. PMID 22955988.
- Dieci G, Fiorino G, Castelnuovo M, Teichmann M, Pagano A (December 2007). "The expanding RNA polymerase III transcriptome". Trends in Genetics 23 (12): 614–22. doi:10.1016/j.tig.2007.09.001. PMID 17977614.
- Dinger, M. E.; Amaral, P. P.; Mercer, T. R.; Mattick, J. S. (2009). "Pervasive transcription of the eukaryotic genome: Functional indices and conceptual implications". Briefings in Functional Genomics and Proteomics 8 (6): 407–423. doi:10.1093/bfgp/elp038. PMID 19770204.
- Eis PS, Tam W, Sun L et al. (March 2005). "Accumulation of miR-155 and BIC RNA in human B cell lymphomas". Proceedings of the National Academy of Sciences of the United States of America 102 (10): 3627–32. Bibcode:2005PNAS..102.3627E. doi:10.1073/pnas.0500613102. PMC 552785. PMID 15738415.
- Espinoza CA, Allen TA, Hieb AR, Kugel JF, Goodrich JA (September 2004). "B2 RNA binds directly to RNA polymerase II to repress transcript synthesis". Nature Structural & Molecular Biology 11 (9): 822–9. doi:10.1038/nsmb812. PMID 15300239.
- Espinoza CA, Goodrich JA, Kugel JF (April 2007). "Characterization of the structure, function, and mechanism of B2 RNA, an ncRNA repressor of RNA polymerase II transcription". RNA 13 (4): 583–96. doi:10.1261/rna.310307. PMC 1831867. PMID 17307818.
- Faghihi MA, Modarresi F, Khalil AM et al. (July 2008). "Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase". Nature Medicine 14 (7): 723–30. doi:10.1038/nm1784. PMC 2826895. PMID 18587408.
- Feng J, Bi C, Clark BS, Mady R, Shah P, Kohtz JD (June 2006). "The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator". Genes & Development 20 (11): 1470–84. doi:10.1101/gad.1416106. PMC 1475760. PMID 16705037.
- Fournier C, Goto Y, Ballestar E et al. (December 2002). "Allele-specific histone lysine methylation marks regulatory regions at imprinted mouse genes". The EMBO Journal 21 (23): 6560–70. doi:10.1093/emboj/cdf655. PMC 136958. PMID 12456662.
- Fu X, Ravindranath L, Tran N, Petrovics G, Srivastava S (March 2006). "Regulation of apoptosis by a prostate-specific and prostate cancer-associated noncoding gene, PCGEM1". DNA and Cell Biology 25 (3): 135–41. doi:10.1089/dna.2006.25.135. PMID 16569192.
- Golden DE, Gerbasi VR, Sontheimer EJ (August 2008). "An inside job for siRNAs". Molecular Cell 31 (3): 309–12. doi:10.1016/j.molcel.2008.07.008. PMC 2675693. PMID 18691963.
- Goodrich JA, Kugel JF (August 2006). "Non-coding-RNA regulators of RNA polymerase II transcription". Nature Reviews Molecular Cell Biology 7 (8): 612–6. doi:10.1038/nrm1946. PMID 16723972.
- Hesman Saey, Tina (17 December 2011). "Missing Lincs". Science News 180 (13): 22–25. doi:10.1002/scin.5591801327.
- Ishii N, Ozaki K, Sato H et al. (2006). "Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction". Journal of Human Genetics 51 (12): 1087–99. doi:10.1007/s10038-006-0070-9. PMID 17066261.
- Jarinova O, Stewart AF, Roberts R et al. (October 2009). "Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus". Arteriosclerosis, Thrombosis, and Vascular Biology 29 (10): 1671–77. doi:10.1161/ATVBAHA.109.189522. PMID 19592466.
- Kapranov P, Cheng J, Dike S et al. (June 2007). "RNA maps reveal new RNA classes and a possible function for pervasive transcription". Science 316 (5830): 1484–8. Bibcode:2007Sci...316.1484K. doi:10.1126/science.1138341. PMID 17510325.
- Kapranov P, Willingham AT, Gingeras TR (June 2007). "Genome-wide transcription and the implications for genomic organization". Nature Reviews. Genetics 8 (6): 413–23. doi:10.1038/nrg2083. PMID 17486121.
- Kapranov P, St Laurent G, Raz T et al. (2010). "The majority of total nuclear-encoded non-ribosomal RNA in a human cell is 'dark matter' un-annotated RNA". BMC Biol. 8: 149. doi:10.1186/1741-7007-8-149. PMC 3022773. PMID 21176148. Erratum in: BMC Biol. 2011;9:86.
- Katayama S, Tomaru Y, Kasukawa T et al. (September 2005). "Antisense transcription in the mammalian transcriptome". Science 309 (5740): 1564–6. Bibcode:2005Sci...309.1564R. doi:10.1126/science.1112009. PMID 16141073.
- Kiefer JC (April 2007). "Epigenetics in development". Developmental Dynamics 236 (4): 1144–56. doi:10.1002/dvdy.21094. PMID 17304537.
- Kim (February 2010). "Evidence for bacterial origin of heat shock RNA-1". RNA 16 (2): 274–279. doi:10.1261/rna.1879610. PMC 2811656. PMID 20040589.
- Kwek KY, Murphy S, Furger A et al. (November 2002). "U1 snRNA associates with TFIIH and regulates transcriptional initiation". Nature Structural Biology 9 (11): 800–5. doi:10.1038/nsb862. PMID 12389039.
- Lander ES, Linton LM, Birren B et al. (February 2001). "Initial sequencing and analysis of the human genome". Nature 409 (6822): 860–921. doi:10.1038/35057062. PMID 11237011.
- Lee JS, Burkholder GD, Latimer LJ, Haug BL, Braun RP (February 1987). "A monoclonal antibody to triplex DNA binds to eucaryotic chromosomes". Nucleic Acids Research 15 (3): 1047–61. doi:10.1093/nar/15.3.1047. PMC 340507. PMID 2434928.
- Lewejohann L, Skryabin BV, Sachser N et al. (September 2004). "Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice". Behavioural Brain Research 154 (1): 273–89. doi:10.1016/j.bbr.2004.02.015. PMID 15302134.
- Li J, Witte DP, Van Dyke T, Askew DS (April 1997). "Expression of the putative proto-oncogene His-1 in normal and neoplastic tissues". The American Journal of Pathology 150 (4): 1297–305. PMC 1858164. PMID 9094986.
- Lin R, Maeda S, Liu C, Karin M, Edgington TS (February 2007). "A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas". Oncogene 26 (6): 851–8. doi:10.1038/sj.onc.1209846. PMID 16878148.
- lincRNA homepage of the Rinn Lab
- Liu WM, Chu WM, Choudary PV, Schmid CW (May 1995). "Cell stress and translational inhibitors transiently increase the abundance of mammalian SINE transcripts". Nucleic Acids Research 23 (10): 1758–65. doi:10.1093/nar/23.10.1758. PMC 306933. PMID 7784180.
- Liu Y, Sanoff HK, Cho H et al. (April 2009). "INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis". PloS One 4 (4): e5027. Bibcode:2009PLoSO...4.5027L. doi:10.1371/journal.pone.0005027. PMC 2660422. PMID 19343170.
- Mancini-Dinardo D, Steele SJ, Levorse JM, Ingram RS, Tilghman SM (May 2006). "Elongation of the Kcnq1ot1 transcript is required for genomic imprinting of neighboring genes". Genes & Development 20 (10): 1268–82. doi:10.1101/gad.1416906. PMC 1472902. PMID 16702402.
- Mariner PD, Walters RD, Espinoza CA et al. (February 2008). "Human Alu RNA is a modular transacting repressor of mRNA transcription during heat shock". Molecular Cell 29 (4): 499–509. doi:10.1016/j.molcel.2007.12.013. PMID 18313387.
- Martianov I, Ramadass A, Serra Barros A, Chow N, Akoulitchev A (February 2007). "Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript". Nature 445 (7128): 666–70. doi:10.1038/nature05519. PMID 17237763.
- Mattick JS (October 2003). "Challenging the dogma: the hidden layer of non-protein-coding RNAs in complex organisms". BioEssays 25 (10): 930–9. doi:10.1002/bies.10332. PMID 14505360.
- Mazo A, Hodgson JW, Petruk S, Sedkov Y, Brock HW (August 2007). "Transcriptional interference: an unexpected layer of complexity in gene regulation". Journal of Cell Science 120 (Pt 16): 2755–61. doi:10.1242/jcs.007633. PMID 17690303.
- McPherson R, Pertsemlidis A, Kavaslar N et al. (May 2007). "A Common Allele on Chromosome 9 Associated with Coronary Heart Disease". Science 316 (5830): 1488–91. Bibcode:2007Sci...316.1488M. doi:10.1126/science.1142447. PMC 2711874. PMID 17478681.
- Mercer, T. R.; Dinger, M. E.; Mattick, J. S. (2009). "Long non-coding RNAs: Insights into functions". Nature Reviews Genetics 10 (3): 155–159. doi:10.1038/nrg2521. PMID 19188922.
- Mikkelsen TS, Ku M, Jaffe DB et al. (August 2007). "Genome-wide maps of chromatin state in pluripotent and lineage-committed cells". Nature 448 (7153): 553–60. Bibcode:2007Natur.448..553M. doi:10.1038/nature06008. PMC 2921165. PMID 17603471.
- Mitsuya K, Meguro M, Lee MP et al. (July 1999). "LIT1, an imprinted antisense RNA in the human KvLQT1 locus identified by screening for differentially expressed transcripts using monochromosomal hybrids". Human Molecular Genetics 8 (7): 1209–17. doi:10.1093/hmg/8.7.1209. PMID 10369866.
- Mohammad F, Pandey RR, Nagano T et al. (June 2008). "Kcnq1ot1/Lit1 noncoding RNA mediates transcriptional silencing by targeting to the perinucleolar region". Molecular and Cellular Biology 28 (11): 3713–28. doi:10.1128/MCB.02263-07. PMC 2423283. PMID 18299392.
- Morey C, Navarro P, Debrand E, Avner P, Rougeulle C, Clerc P (February 2004). "The region 3' to Xist mediates X chromosome counting and H3 Lys-4 dimethylation within the Xist gene". The EMBO Journal 23 (3): 594–604. doi:10.1038/sj.emboj.7600071. PMC 1271805. PMID 14749728.
- Munroe SH, Lazar MA (25 November 1991). "Inhibition of c-erbA mRNA splicing by a naturally occurring antisense RNA". The Journal of Biological Chemistry 266 (33): 22083–6. PMID 1657988.
- Muslimov IA, Banker G, Brosius J, Tiedge H (June 1998). "Activity-dependent regulation of dendritic BC1 RNA in hippocampal neurons in culture". The Journal of Cell Biology 141 (7): 1601–11. doi:10.1083/jcb.141.7.1601. PMC 1828539. PMID 9647652.
- Nesterova TB, Barton SC, Surani MA, Brockdorff N (July 2001). "Loss of Xist imprinting in diploid parthenogenetic preimplantation embryos". Developmental Biology 235 (2): 343–50. doi:10.1006/dbio.2001.0295. PMID 11437441.
- Nickerson JA, Krochmalnic G, Wan KM, Penman S (January 1989). "Chromatin architecture and nuclear RNA". Proceedings of the National Academy of Sciences of the United States of America 86 (1): 177–81. Bibcode:1989PNAS...86..177N. doi:10.1073/pnas.86.1.177. PMC 286427. PMID 2911567.
- Ogawa Y, Sun BK, Lee JT (June 2008). "Intersection of the RNA interference and X-inactivation pathways". Science 320 (5881): 1336–41. Bibcode:2008Sci...320.1336O. doi:10.1126/science.1157676. PMC 2584363. PMID 18535243.
- Pagano JM, Farley BM, McCoig LM, Ryder SP (March 2007). "Molecular basis of RNA recognition by the embryonic polarity determinant MEX-5". The Journal of Biological Chemistry 282 (12): 8883–94. doi:10.1074/jbc.M700079200. PMID 17264081.
- Pang KC, Frith MC, Mattick JS (January 2006). "Rapid evolution of noncoding RNAs: lack of conservation does not mean lack of function". Trends in Genetics 22 (1): 1–5. doi:10.1016/j.tig.2005.10.003. PMID 16290135.
- Panganiban G, Rubenstein JL (1 October 2002). "Developmental functions of the Distal-less/Dlx homeobox genes". Development 129 (19): 4371–86. PMID 12223397.
- Pasmant E, Laurendeau I, Héron D, Vidaud M, Vidaud D, Bièche I (April 2007). "Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF". Cancer Research 67 (8): 3963–9. doi:10.1158/0008-5472.CAN-06-2004. PMID 17440112.
- Pauler FM, Koerner MV, Barlow DP (June 2007). "Silencing by imprinted noncoding RNAs: is transcription the answer?". Trends in Genetics 23 (6): 284–92. doi:10.1016/j.tig.2007.03.018. PMC 2847181. PMID 17445943.
- Pennacchio LA, Ahituv N, Moses AM et al. (November 2006). "In vivo enhancer analysis of human conserved non-coding sequences". Nature 444 (7118): 499–502. Bibcode:2006Natur.444..499P. doi:10.1038/nature05295. PMID 17086198.
- Perkel, Jeffrey M. (2013). "Visiting "Noncodarnia"". BioTechniques (paper) 54 (6): 301–304. doi:10.2144/000114037. PMID 23750541.
"We're calling long noncoding RNAs a class, when actually the only definition is that they are longer than 200 bp," says Ana Marques, a Research Fellow at the University of Oxford who uses evolutionary approaches to understand lncRNA function.
- Pibouin L, Villaudy J, Ferbus D et al. (February 2002). "Cloning of the mRNA of overexpression in colon carcinoma-1: a sequence overexpressed in a subset of colon carcinomas". Cancer Genetics and Cytogenetics 133 (1): 55–60. doi:10.1016/S0165-4608(01)00634-3. PMID 11890990.
- Pollard KS, Salama SR, King B et al. (October 2006). "Forces shaping the fastest evolving regions in the human genome". PLoS Genetics 2 (10): e168. doi:10.1371/journal.pgen.0020168. PMC 1599772. PMID 17040131.
- Pollard KS, Salama SR, Lambert N et al. (September 2006). "An RNA gene expressed during cortical development evolved rapidly in humans". Nature 443 (7108): 167–72. Bibcode:2006Natur.443..167P. doi:10.1038/nature05113. PMID 16915236.
- Ponjavic J, Ponting CP, Lunter G (May 2007). "Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs". Genome Research 17 (5): 556–65. doi:10.1101/gr.6036807. PMC 1855172. PMID 17387145.
- Reinius, B.; Shi, C.; Hengshuo, L.; Sandhu, K.; Radomska, K. J.; Rosen, G. D.; Lu, L.; Kullander, K.; Williams, R. W.; Jazin, E. (2010). "Female-biased expression of long non-coding RNAs in domains that escape X-inactivation in mouse". BMC Genomics 11: 614. doi:10.1186/1471-2164-11-614. PMC 3091755. PMID 21047393.
- Reis EM, Nakaya HI, Louro R et al. (August 2004). "Antisense intronic non-coding RNA levels correlate to the degree of tumor differentiation in prostate cancer". Oncogene 23 (39): 6684–92. doi:10.1038/sj.onc.1207880. PMID 15221013.
- Rinn JL, Kertesz M, Wang JK et al. (June 2007). "Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs". Cell 129 (7): 1311–23. doi:10.1016/j.cell.2007.05.022. PMC 2084369. PMID 17604720.
- Rodríguez-Campos A, Azorín F (2007). "RNA is an integral component of chromatin that contributes to its structural organization". PLoS ONE 2 (11): e1182. Bibcode:2007PLoSO...2.1182R. doi:10.1371/journal.pone.0001182. PMC 2063516. PMID 18000552.
- Sanchez-Elsner T, Gou D, Kremmer E, Sauer F (February 2006). "Noncoding RNAs of trithorax response elements recruit Drosophila Ash1 to Ultrabithorax". Science 311 (5764): 1118–23. Bibcode:2006Sci...311.1118S. doi:10.1126/science.1117705. PMID 16497925.
- Schoeftner S, Blasco MA (February 2008). "Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II". Nature Cell Biology 10 (2): 228–36. doi:10.1038/ncb1685. PMID 18157120.
- Shamovsky I, Nudler E (October 2006). "Gene control by large noncoding RNAs". Science's STKE : Signal Transduction Knowledge Environment 2006 (355): pe40. doi:10.1126/stke.3552006pe40. PMID 17018852.
- Shamovsky I, Nudler E (February 2008). "Modular RNA heats up". Molecular Cell 29 (4): 415–7. doi:10.1016/j.molcel.2008.02.001. PMID 18313380.
- Shirasawa S, Harada H, Furugaki K et al. (October 2004). "SNPs in the promoter of a B cell-specific antisense transcript, SAS-ZFAT, determine susceptibility to autoimmune thyroid disease". Human Molecular Genetics 13 (19): 2221–31. doi:10.1093/hmg/ddh245. PMID 15294872.
- Siepel A, Bejerano G, Pedersen JS et al. (August 2005). "Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes". Genome Research 15 (8): 1034–50. doi:10.1101/gr.3715005. PMC 1182216. PMID 16024819.
- Singh K, Carey M, Saragosti S, Botchan M (1985). "Expression of enhanced levels of small RNA polymerase III transcripts encoded by the B2 repeats in simian virus 40-transformed mouse cells". Nature 314 (6011): 553–6. Bibcode:1985Natur.314..553S. doi:10.1038/314553a0. PMID 2581137.
- Sleutels F, Zwart R, Barlow DP (February 2002). "The non-coding Air RNA is required for silencing autosomal imprinted genes". Nature 415 (6873): 810–3. doi:10.1038/415810a. PMID 11845212.
- Smith NG, Brandström M, Ellegren H (November 2004). "Evidence for turnover of functional noncoding DNA in mammalian genome evolution". Genomics 84 (5): 806–13. doi:10.1016/j.ygeno.2004.07.012. PMID 15475259.
- Sonkoly E, Bata-Csorgo Z, Pivarcsi A et al. (June 2005). "Identification and characterization of a novel, psoriasis susceptibility-related noncoding RNA gene, PRINS". The Journal of Biological Chemistry 280 (25): 24159–67. doi:10.1074/jbc.M501704200. PMID 15855153.
- Struhl K (February 2007). "Transcriptional noise and the fidelity of initiation by RNA polymerase II". Nature Structural & Molecular Biology 14 (2): 103–5. doi:10.1038/nsmb0207-103. PMID 17277804.
- Tang RB, Wang HY, Lu HY et al. (February 2005). "Increased level of polymerase III transcribed Alu RNA in hepatocellular carcinoma tissue". Molecular Carcinogenesis 42 (2): 93–6. doi:10.1002/mc.20057. PMID 15593371.
- Tiedge H, Chen W, Brosius J (1 June 1993). "Primary structure, neural-specific expression, and dendritic location of human BC200 RNA". Journal of Neuroscience 13 (6): 2382–90. PMID 7684772.
- Tiedge H, Fremeau RT, Weinstock PH, Arancio O, Brosius J (March 1991). "Dendritic location of neural BC1 RNA". Proceedings of the National Academy of Sciences of the United States of America 88 (6): 2093–7. Bibcode:1991PNAS...88.2093T. doi:10.1073/pnas.88.6.2093. PMC 51175. PMID 1706516.
- Torarinsson E, Sawera M, Havgaard JH, Fredholm M, Gorodkin J (July 2006). "Thousands of corresponding human and mouse genomic regions unalignable in primary sequence contain common RNA structure". Genome Research 16 (7): 885–9. doi:10.1101/gr.5226606. PMC 1484455. PMID 16751343.
- Torarinsson E, Sawera M, Havgaard JH, Fredholm M, Gorodkin J (July 2006). "Thousands of corresponding human and mouse genomic regions unalignable in primary sequence contain common RNA structure". Genome Research 16 (7): 885–9. doi:10.1101/gr.5226606. PMC 1484455. PMID 16751343.
- Tufarelli C, Stanley JA, Garrick D et al. (June 2003). "Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease". Nature Genetics 34 (2): 157–65. doi:10.1038/ng1157. PMID 12730694.
- Umlauf D, Goto Y, Cao R et al. (December 2004). "Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes". Nature Genetics 36 (12): 1296–300. doi:10.1038/ng1467. PMID 15516932.
- Visel A, Prabhakar S, Akiyama JA et al. (February 2008). "Ultraconservation identifies a small subset of extremely constrained developmental enhancers". Nature Genetics 40 (2): 158–60. doi:10.1038/ng.2007.55. PMC 2647775. PMID 18176564.
- Wang H, Iacoangeli A, Lin D et al. (December 2005). "Dendritic BC1 RNA in translational control mechanisms". The Journal of Cell Biology 171 (5): 811–21. doi:10.1083/jcb.200506006. PMC 1828541. PMID 16330711.
- Wang X, Arai S, Song X et al. (July 2008). "Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription". Nature 454 (7200): 126–30. Bibcode:2008Natur.454..126W. doi:10.1038/nature06992. PMC 2823488. PMID 18509338.
- Waterston RH, Lindblad-Toh K, Birney E et al. (December 2002). "Initial sequencing and comparative analysis of the mouse genome". Nature 420 (6915): 520–62. Bibcode:2002Natur.420..520W. doi:10.1038/nature01262. PMID 12466850.
- Wutz A, Gribnau J (October 2007). "X inactivation Xplained". Current Opinion in Genetics & Development 17 (5): 387–93. doi:10.1016/j.gde.2007.08.001. PMID 17869504.
- Wutz A, Rasmussen TP, Jaenisch R (February 2002). "Chromosomal silencing and localization are mediated by different domains of Xist RNA". Nature Genetics 30 (2): 167–74. doi:10.1038/ng820. PMID 11780141.
- Yang S, Tutton S, Pierce E, Yoon K (November 2001). "Specific double-stranded RNA interference in undifferentiated mouse embryonic stem cells". Molecular and Cellular Biology 21 (22): 7807–16. doi:10.1128/MCB.21.22.7807-7816.2001. PMC 99950. PMID 11604515.
- Yik JH, Chen R, Nishimura R, Jennings JL, Link AJ, Zhou Q (October 2003). "Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA". Molecular Cell 12 (4): 971–82. doi:10.1016/S1097-2765(03)00388-5. PMID 14580347.
- Yu W, Gius D, Onyango P et al. (January 2008). "Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA". Nature 451 (7175): 202–6. Bibcode:2008Natur.451..202Y. doi:10.1038/nature06468. PMC 2743558. PMID 18185590.
- Zearfoss NR, Chan AP, Kloc M, Allen LH, Etkin LD (April 2003). "Identification of new Xlsirt family members in the Xenopus laevis oocyte". Mechanisms of Development 120 (4): 503–9. doi:10.1016/S0925-4773(02)00459-8. PMID 12676327.
- Zwart R, Sleutels F, Wutz A, Schinkel AH, Barlow DP (September 2001). "Bidirectional action of the Igf2r imprint control element on upstream and downstream imprinted genes". Genes & Development 15 (18): 2361–6. doi:10.1101/gad.206201. PMC 312779. PMID 11562346.
- LncRNA2Target database: providing the manually curated target genes of long non-coding RNAs (lncRNAs).
- ChIPBase database: decodes the transcriptional regulation of lncRNAs from ChIP-Seq and provides expression profiles of lncRNAs (lincRNAs) from RNA-Seq data across 22 tissues.
- lncRNAdb database: providing comprehensive annotations of functional long non-coding RNAs (lncRNAs).
- Long RNA Synthesis: chemical long RNA synthesis and long RNA synthesis by transcription.
- MONOCLdb: provides the annotations and expression profiles of several thousands mouse long non-coding RNAs (lncRNAs) involved in Influenza and SARS-CoV infections.
- HGNC: provides approved gene names for human long non-coding RNAs (lncRNAs) - Wright, MW (Apr 9, 2014). "A short guide to long non-coding RNA gene nomenclature.". Human genomics 8: 7. doi:10.1186/1479-7364-8-7. PMC 4021045. PMID 24716852.
- LncRNAWiki: a wiki-based database for management of human long non-coding RNAs (lncRNAs).