Gene regulation by the act of long non-coding RNA transcription
© Kornienko et al.; licensee BioMed Central Ltd. 2013
Received: 18 January 2013
Accepted: 15 May 2013
Published: 30 May 2013
Long non-protein-coding RNAs (lncRNAs) are proposed to be the largest transcript class in the mouse and human transcriptomes. Two important questions are whether all lncRNAs are functional and how they could exert a function. Several lncRNAs have been shown to function through their product, but this is not the only possible mode of action. In this review we focus on a role for the process of lncRNA transcription, independent of the lncRNA product, in regulating protein-coding-gene activity in cis. We discuss examples where lncRNA transcription leads to gene silencing or activation, and describe strategies to determine if the lncRNA product or its transcription causes the regulatory effect.
KeywordsGene expression regulation Histone modifications lincRNA lncRNA Silencing Transcriptional interference
LncRNAs - a new layer of genome regulatory information
It is now well appreciated that less than two percent of the human genome codes for proteins and the majority of the genome gives rise to non-protein-coding RNAs (ncRNAs) , which are predicted to play essential roles in a variety of biological processes [2, 3].
The focus of this review is long ncRNAs (known as lncRNAs), which constitute the biggest class of ncRNAs with approximately 10,000 lncRNA genes so far annotated in humans . lncRNAs are RNA polymerase II (RNAPII) transcripts that lack an open reading frame and are longer than 200 nucleotides. This size cut-off distinguishes lncRNAs from small RNAs such as microRNAs, piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs) and small interfering RNAs (siRNAs) and arises from RNA preparation methods that capture RNA molecules above this size. Although the function of most lncRNAs is unknown, the number of characterized lncRNAs is growing and many publications suggest they play roles in negatively or positively regulating gene expression in development, differentiation and human disease [2, 5–10]. lncRNAs may regulate protein-coding (pc) gene expression at both the posttranscriptional and transcriptional level. Posttranscriptional regulation could occur by lncRNAs acting as competing endogenous RNAs to regulate microRNA levels as well as by modulating mRNA stability and translation by homologous base pairing, or as in the example of NEAT1 that is involved in nuclear retention of mRNAs . In this review we focus on the regulation at the transcriptional level.
Modes of transcriptional regulation by lncRNAs
Regulation of transcription is considered to be an interplay of tissue and developmental-specific transcription factors (TFs) and chromatin modifying factors acting on enhancer and promoter sequences to facilitate the assembly of the transcription machinery at gene promoters. With a growing number of lncRNAs implicated in transcriptional gene regulation, this view may need refinement to include networks of tissue and developmental-stage specific lncRNAs that complement known regulators to tightly control gene expression and thereby organism complexity [12, 13]. Transcriptional regulation by lncRNAs could work either in cis or in trans, and could negatively or positively control pc gene expression. lncRNAs work in cis when their effects are restricted to the chromosome from which they are transcribed, and work in trans when they affect genes on other chromosomes.
Regulation in trans
Regulation in trans can also act locus-specifically. While the ability of lncRNAs to act locus-specifically to regulate a set of genes was first demonstrated for imprinted genes where lncRNA expression was shown to silence from one to ten flanking genes in cis[18–20], lncRNAs that lie outside imprinted gene clusters, such as the HOTAIR lncRNA, were later found also to have locus-specific action. HOTAIR is expressed from the HOXC cluster and was shown to repress transcription in trans across 40 kb of the HOXD cluster . HOTAIR interacts with Polycomb repressive complex 2 (PRC2) and is required for repressive histone H3 lysine-27 trimethylation (H3K27me3) of the HOXD cluster. Targeting of epigenetic modifiers (EMs) by lncRNAs provided a much sought after model to explain how EMs gain locus specificity (Figure 1d), and has since been suggested as a general mechanism for trans-acting lncRNAs [22, 23].
Regulation in cis
In contrast to trans-acting lncRNAs, which act via their RNA product, cis-acting lncRNAs have the possibility to act in two fundamentally different modes. The first mode depends on a lncRNA product. The major example of general cis-regulation is induction of X inactivation by the Xist lncRNA in female mammals. Xist is expressed from one of the two X chromosomes and induces silencing of the whole chromosome  (Figure 1c). As an example of locus-specific regulation it has been proposed that enhancer RNAs activate corresponding genes in cis via their product . A well-studied cis-acting lncRNA acting through its product is the human HOTTIP lncRNA that is expressed in the HOXA cluster and activates transcription of flanking genes. HOTTIP was shown to act by binding WDR5 in the MLL histone modifier complex, thereby bringing histone H3 lysine-4 trimethylation (H3K4me3) to promoters of the flanking genes . Such a mechanism in which a nascent lncRNA transcript binds and delivers epigenetic modifiers to its target genes while still attached to the elongating RNAPII is generally termed ‘tethering’ and is often used to explain cis-regulation by lncRNAs [23, 27] (Figure 1e). It was also proposed to act in plants. In Arabidopsis thaliana, the COLDAIR lncRNA is initiated from an intron of the FLC pc gene and silences it by targeting repressive chromatin marks to the locus to control flowering time .
In contrast, the second mode of cis regulation by lncRNAs involves the process of transcription itself, which is a priori cis-acting (Figure 1f). Several lines of evidence suggest that the mere process of lncRNA transcription can affect gene expression if RNAPII traverses a regulatory element or changes general chromatin organization of the locus. In this review we discuss this underestimated role for lncRNA transcription in inducing protein-coding gene silencing or activation in cis, and overview possible mechanisms for this action in mammalian and non-mammalian organisms. Finally, we describe experimental strategies to distinguish lncRNAs acting as a transcript from those acting through transcription.
Mechanisms by which lncRNA transcriptionsilences gene expression
Transcription-mediated silencing, also referred to as ‘transcriptional interference’ (TI), is defined here as a case in which the act of transcription of one gene can repress in cis the functional transcription of another gene [29, 30]. TI has been reported in unicellular and multicellular organisms . Mechanistic details are still largely unclear, but TI could theoretically act at several stages in transcription: by influencing enhancer or promoter activity or by blocking RNAPII elongation, splicing or polyadenylation. All that would be required is that the RNA polymerase (RNAPII) initiated from an 'interfering' promoter traverses a 'sensitive' DNA regulatory sequence. TI has mainly been reported at overlapped promoters [31–35], but there are also examples where TI acts downstream of the promoter. In mouse, overlapping transcription controls polyadenylation choice of two imprinted genes [36, 37]. In Saccharomyces cerevisiae, collisions between elongating antisense RNAPIIs can lead to stalling of both polymerases that is resolved by ubiquitylation-directed proteolysis, and this has been proposed to be a regulatory mechanism . However, it is unknown if RNAPII collisions occur sufficiently frequently in vivo in yeast or other organisms to offer a means of regulating convergent genes, or if this mechanism could lead to an interfering RNAPII eliminating its sensitive collision partner. Despite these examples, the most common reports of TI concern an overlapped promoter, and in the following sections we describe studies investigating the molecular mechanisms underlying interference at the promoter.
Transcriptional interference acting by promoter nucleosome repositioning
Transcriptional interference acting by promoter histone modifications
Promoter associated nucleosomes carry post-translational histone tail modifications that reflect the activity state of the promoter and also influence accessibility of DNA binding factors involved in transcription . Active gene promoters correlate with H3 and H4 acetylation and with H3K4me3, while inactive promoters do not and, in mammals, they also gain repressive histone marks such as H3K9me3 or H3K27me3. Some histone modifying enzymes have been shown to bind and travel with elongating RNAPII [56, 57], so it is possible that lncRNA transcription can induce TI by affecting histone modifications at the promoter of an overlapped target gene. For example, in yeast the SET1/2 methyltransferases, which induce H3K4me2 and H3K36me3 in the body of transcribed genes, bind and travel with elongating RNAPII [58–60]. These modifications in turn recruit the SET3C/RPD3S histone deacetylase complexes to create a chromatin environment repressive for transcription initiation [61–63].
Two studies indicate that this is a mechanism used by lncRNAs to induce TI in yeast. In the first study the IME1 pc gene, which induces gametogenesis in diploid S. cerevisiae cells but is repressed in haploid cells, was shown to be silenced by the IRT1 lncRNA that overlaps its promoter . Genetic experiments repositioning the IRT1 lncRNA distant from IME1 on the same chromosome showed that IRT1 transcriptional overlap of the IME1 promoter is necessary for silencing. Interestingly, the instability of the IRT1 lncRNA product and its non-specific cellular localization indicated the lncRNA product is unlikely to play a role in the silencing mechanism. Instead, IRT1 lncRNA transcription through the IME1 promoter reduced recruitment of the essential POG1 transcription factor, increased nucleosome density and induced the SET1/2 mediated cascades of histone modifications, which were shown to be necessary for silencing  (Figure 2b). In the second study lncRNA transcription was shown to be causative for silencing of the GAL1 and GAL10 genes, involved in galactose metabolism in S. cerevisiae. GAL10 and GAL1 are divergently transcribed from a bidirectional promoter. The 4 kb lncRNA, called GAL10-ncRNA, initiates in the body of the GAL10 gene, and is transcribed through the GAL10/GAL1 promoter antisense to the GAL10 gene. GAL10-ncRNA transcription induces SET2-mediated establishment of H3K36me3 along its gene body, thereby recruiting RPD3S-dependent deacetylation that resulted in reduced transcription factor binding and repression of the GAL1/GAL10 promoter . Both SET3C and RPD3S are proposed to have a general role in repressing cryptic promoters within gene bodies [61, 66] and a genome-wide study implied a role for SET3C in overlapping lncRNA-mediated silencing of a set of pc genes in yeast . This indicates that the mechanism described above might be widely used to control gene expression in yeast. Although similar studies have not been described for the mammalian genome, H3K36me3 marks the body of transcribed genes in mammals, raising the possibility that such TI mechanisms could be conserved [56, 57].
Transcriptional interference acting by promoter DNA methylation
In mammalian genomes DNA methylation is generally associated with silent CpG island promoters, but the majority of CpG island promoters remain methylation free independent of their expression status [67–69]. The process of de novo methylation depends on the DNMT3A/3B methyltransferases and the catalytically inactive DNMT3L homologue and requires histones lacking H3K4me3, ensuring that active promoters remain methylation-free . Notably, while DNA methylation at the promoter blocks transcription initiation, methylation in the gene body does not. Two important examples in humans based on genetic analyses indicate that DNA methylation can be involved in TI-induced silencing, although the causality between DNA methylation and silencing is still a matter of discussion . One study of a patient with inherited α-thalassemia identified a deletion of the LUC7L 3' end that allowed aberrant transcription of LUC7L through the downstream HBA2 gene, causing its silencing and the disease phenotype  (Figure 2c). Mouse models that mimicked the deleted genomic locus showed that the main cause of silencing was the acquisition of DNA methylation at the HBA2 promoter. Notably, DNA methylation acquisition was not simply the consequence of an inactive promoter, as removal of HBA2 transcription by deleting its TATA box did not induce methylation. The sequence of the LUC7L gene and thus the aberrant RNA product was also not essential for HBA2 silencing, as replacing the LUC7L gene body with another protein-coding gene did not remove the repressive effect. In a second example, a subset of Lynch syndrome patients display DNA methylation and inactivation of the mismatch repair MSH2 gene that correlates with aberrant transcription from the flanking EPCAM gene that carries a 3' deletion .
In both these examples, the molecular details of methylation establishment and the mechanism by which the methylation machinery targets the overlapped promoter are yet unknown. However, the data so far show that it is a cis-acting mechanism as only the allele carrying the deletion silences the overlapped protein-coding gene. In addition, although a role for the aberrant RNA product was not excluded, it appears unlikely that mutation-induced transcription of two independent intergenic chromosomal regions in the described diseases produces lncRNA products with similar repressive functions. Interestingly, the silencing of imprinted pc genes by lncRNAs is also often correlated with the gain of DNA methylation on the silent pc gene promoter . In the case of the Igf2r gene, this DNA methylation mark is not necessary for initiation or maintenance of the silent state but seems to play a role in re-enforcing the silent state [35, 74].
Transcriptional interference in the absence of chromatin changes at the silenced promoter
To date, other examples of lncRNAs acting by this mechanism in mammals are lacking. It has been suggested that silencing of an alternative promoter of the mouse fpgs pc gene is an example of transcription inducing silencing without introducing chromatin changes , but this system has not been subject to a similar genetic analysis and alternative explanations remain possible. How RNAPII from an interfering promoter is able to suppress functional transcription of the overlapped promoter remains to be determined, but stalling of the interfering RNAPII elongating over the sensitive promoter has been suggested to block access of essential TFs [30, 83]. This mechanism should not be confused with the phenomenon of genome-wide RNAPII pausing at promoters, which represents an intermediate step between RNAPII initiation and elongation phases and might be a common mechanism regulating differential gene expression in metazoans [84, 85].
The above examples describe repressive effects from RNAPII transcribing lncRNAs through promoters of silenced genes. However, transcriptional interference might also disrupt enhancer function when RNAPII traverses an enhancer, and this is an attractive model to explain the repression of a cluster of genes by a lncRNA in a tissue-specific manner  (Figure 3b). This situation arises in two imprinted gene clusters where the Airn and Kcnq1ot1 lncRNAs each overlap one gene, but silence multiple genes in cis in a tissue-specific manner. The repressive histone EHMT2 methyltransferase has been shown to be necessary in the placenta to silence one of the three genes controlled by Airn. The Kcnq1ot1 lncRNA has been shown to silence multiple genes in placental cells by the action of repressive POLYCOMB histone modifying enzymes [87, 88]. In both cases, a direct role for the lncRNA in targeting the histone modifying complexes was proposed, based on the findings that the lncRNAs interact with the respective histone modifying complex. This correlation-based evidence is, however, not sufficient to rule out the possibility that both lncRNAs silence distant genes by transcription alone (reviewed in [75, 76]). In support of a transcription-based model, it was shown that Kcnq1ot1 silences at least one gene by regulating chromatin flexibility and access to enhancers . This is consistent with a two-step model whereby lncRNA transcription initiates silencing of non-overlapped genes by enhancer interference, then repressive histone modifying enzymes maintain that silencing.
lncRNA transcription creating a permissive chromatin environment
lncRNA transcription and locus activation
Other examples indicate that lncRNA transcription activates gene expression by blocking access of repressor complexes to chromatin. In Drosophila, intergenic non-coding transcription at the BITHORAX complex (BX-C) is implicated in reversing POLYCOMB group (PCG)-mediated gene silencing and is correlated with an active chromatin state . This mode of action was later suggested to be a general mechanism where the act of transcription serves as an epigenetic switch that relieves PCG-mediated gene silencing by recruiting epigenetic modifiers to induce gene expression and generate stable and heritable active chromatin . In line with this hypothesis, intergenic transcription through PCG response elements (PREs) in the BX-C cluster is not only found during embryogenesis but also in late stage larvae, indicating that continuous transcription is required to keep genes active . In mouse and human, a similar role for PRE transcription has been proposed. An analysis of lncRNA transcription in the human HOXA cluster revealed a positive correlation between lncRNA transcription and the loss of PCG/chromatin interactions that precedes HOXA gene activation . Additionally, lncRNAs have been identified at promoter regions of PCG-regulated genes in mouse cells; while their role is not yet clear, it has been suggested that they either promote or interfere with PCG binding at target genes [103, 104].
A further example of a lncRNA mediating chromatin opening was described at the S. cerevisiae PHO5 gene. Transcription of an antisense lncRNA that initiates near the 3’end of PHO5 and overlaps its gene body and promoter is associated with rapid activation of PHO5 by enabling nucleosome eviction. Biochemical inhibition of RNAPII elongation as well as genetic disruption of lncRNA elongation demonstrated a direct role in PHO5 activation . The association of lncRNA transcription with gene activation needs, however, to be considered within the framework that most protein-coding gene promoters in yeast and mammalian cells give rise to a bidirectional antisense lncRNA transcript [106, 107]. To date it is unclear if promoter-associated bidirectional lncRNAs represent spurious transcription in the context of open chromatin [108, 109] or is required to maintain open chromatin. In the latter case enhanced TF binding ensures accessible chromatin that allows more constant pc gene expression within a cell population  (Figure 4c).
Strategies for distinguishing a role for the lncRNA product from that of its transcription
Following genome-wide lncRNA mapping, functional studies so far have mainly focused on lncRNA products [7, 111]. As it becomes clear that lncRNAs can act through their transcription, it is important to identify strategies to determine the function and mode of action of each particular lncRNA. One common starting point to determine lncRNA function has been RNA interference (RNAi)-mediated knockdown, despite long-standing observations that the RNAi machinery in mammalian cells is located in the cytoplasm . While there is evidence that some RNA-induced silencing complex (RISC) components are found in the nucleus, functional complexes are specifically loaded in the cytoplasm, prohibiting the application of RNAi strategies for nuclear localized lncRNAs . In contrast, antisense oligonucleotides (ASO) that work via an RNaseH-dependent pathway will deplete nuclear-localized lncRNAs [114, 115]. However, three additional points of caution should be noted. First, non-specific effects arising from nuclear transfection reagents  have confused some observations. One critical validation step for knockdown studies would be a rescue experiment in which the lncRNA, modified to be invulnerable to the knockdown, is expressed as a transgene under the same transfection conditions . Second, some results have highlighted major differences when functional studies used post-transcriptional depletion strategies in cell lines in contrast to genetic studies in the organism. Notable examples are Neat1, Malat1[116, 118, 119] and Hotair where studies of mice carrying genetically disrupted alleles of these three lncRNAs failed to reproduce phenotypes deduced from cell lines following RNAi, ASO or over-expression studies. Third, while knockdown experiments may elucidate the function of lncRNAs acting through their product, the function of cis-acting lncRNAs that depend only on transcription will not be disturbed.
Features such as subcellular localization, half-life and steady-state abundance would form a good basis to allow functional tests to be designed. In addition, knowledge of the lncRNA splicing efficiency, conservation of splicing pattern in multiple tissues and species, an estimation of transcript repeat content and, finally, an accurate mapping of lncRNA 5' and 3' ends are essential preliminary steps. We have previously proposed that a subclass of lncRNAs, ‘macro’ lncRNAs, show RNA biology hallmarks such as inefficient splicing, extreme length, high repeat content, lack of conservation and a short half-life. These features are also indicators that the lncRNA product is less important than the act of transcription . Once RNA biology features are known, experiments can be designed to distinguish between a role for the lncRNA product or its transcription.
From the caveats of posttranscriptional knockdown experiments described above, it becomes clear that genetic strategies are optimal for testing lncRNA function. These strategies include manipulating the endogenous locus to delete the promoter or the whole gene or to shorten its length using inserted polyadenylation signals, as described for several examples above. This may appear a formidable task with the appreciation that lncRNAs in the human genome may outnumber protein-coding genes ; however, suitable cell systems already exist. These include the use of haploid cell lines with transcriptional stop signal insertions in most human genes that are screened by RNA sequencing , gene targeting by engineered zinc-finger nucleases  or CRISPR systems  or the use of mouse embryonic stem cells that have efficient rates of homologous targeting [125, 126].
We thank Quanah Hudson and Federica Santoro for comments on the manuscript. The authors are partly supported by the Austrian Science Fund: FWF SFB-F43 and FWF W1207-BO9. PG is recipient of a DOC Fellowship of the Austrian Academy of Sciences.
- Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Röder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Bar NS, Batut P, Bell K, Bell I, Chakrabortty S, Chen X, Chrast J, Curado J: Landscape of transcription in human cells. Nature. 2012, 489: 101-108.PubMed CentralPubMedGoogle Scholar
- Wilusz JE, Sunwoo H, Spector DL: Long noncoding RNAs: functional surprises from the RNA world. Genes Dev. 2009, 23: 1494-1504.PubMed CentralPubMedGoogle Scholar
- Pauli A, Rinn JL, Schier AF: Non-coding RNAs as regulators of embryogenesis. Nat Rev Genet. 2011, 12: 136-149.PubMed CentralPubMedGoogle Scholar
- Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG, Lagarde J, Veeravalli L, Ruan X, Ruan Y, Lassmann T, Carninci P, Brown JB, Lipovich L, Gonzalez JM, Thomas M, Davis CA, Shiekhattar R, Gingeras TR, Hubbard TJ, Notredame C, Harrow J, Guigó R: The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 2012, 22: 1775-1789.PubMed CentralPubMedGoogle Scholar
- Taft RJ, Pang KC, Mercer TR, Dinger M, Mattick JS: Non-coding RNAs: regulators of disease. J Pathol. 2010, 220: 126-139.PubMedGoogle Scholar
- Huarte M, Rinn JL: Large non-coding RNAs: missing links in cancer?. Hum Mol Genet. 2010, 19: R152-R161.PubMed CentralPubMedGoogle Scholar
- Guttman M, Donaghey J, Carey BW, Garber M, Grenier JK, Munson G, Young G, Lucas AB, Ach R, Bruhn L, Yang X, Amit I, Meissner A, Regev A, Rinn JL, Root DE: Lander ES: lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature. 2011, 477: 295-300.PubMed CentralPubMedGoogle Scholar
- Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, Wang Y, Brzoska P, Kong B, Li R, West RB, van de Vijver MJ, Sukumar S, Chang HY: Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010, 464: 1071-1076.PubMed CentralPubMedGoogle Scholar
- Prensner JR, Iyer MK, Balbin OA, Dhanasekaran SM, Cao Q, Brenner JC, Laxman B, Asangani IA, Grasso CS, Kominsky HD, Cao X, Jing X, Wang X, Siddiqui J, Wei JT, Robinson D, Iyer HK, Palanisamy N, Maher CA, Chinnaiyan AM: Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat Biotechnol. 2011, 29: 742-749.PubMed CentralPubMedGoogle Scholar
- Yap KL, Li S, Munoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, Gil J, Walsh MJ, Zhou MM: Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell. 2010, 38: 662-674.PubMed CentralPubMedGoogle Scholar
- Yoon JH, Abdelmohsen K, Gorospe M: Posttranscriptional gene regulation by long noncoding RNA. J Mol Biol. 2012, pii:S0022-2836(12)00896-0Google Scholar
- Mattick JS: Deconstructing the dogma: a new view of the evolution and genetic programming of complex organisms. Ann N Y Acad Sci. 2009, 1178: 29-46.PubMedGoogle Scholar
- Mattick JS, Taft RJ, Faulkner GJ: A global view of genomic information–moving beyond the gene and the master regulator. Trends Genet. 2010, 26: 21-28.PubMedGoogle Scholar
- Peterlin BM, Brogie JE, Price DH: 7SK snRNA: a noncoding RNA that plays a major role in regulating eukaryotic transcription. Wiley Interdiscip Rev RNA. 2012, 3: 92-103.PubMed CentralPubMedGoogle Scholar
- Espinoza CA, Allen TA, Hieb AR, Kugel JF, Goodrich JA: B2 RNA binds directly to RNA polymerase II to repress transcript synthesis. Nat Struct Mol Biol. 2004, 11: 822-829.PubMedGoogle Scholar
- Espinoza CA, Goodrich JA, Kugel JF: Characterization of the structure, function, and mechanism of B2 RNA, an ncRNA repressor of RNA polymerase II transcription. RNA. 2007, 13: 583-596.PubMed CentralPubMedGoogle Scholar
- Yakovchuk P, Goodrich JA, Kugel JF: B2 RNA represses TFIIH phosphorylation of RNA polymerase II. Transcription. 2011, 2: 45-49.PubMed CentralPubMedGoogle Scholar
- Sleutels F, Zwart R, Barlow DP: The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature. 2002, 415: 810-813.PubMedGoogle Scholar
- Mancini-Dinardo D, Steele SJ, Levorse JM, Ingram RS, Tilghman SM: Elongation of the Kcnq1ot1 transcript is required for genomic imprinting of neighboring genes. Genes Dev. 2006, 20: 1268-1282.PubMed CentralPubMedGoogle Scholar
- Williamson CM, Ball ST, Dawson C, Mehta S, Beechey CV, Fray M, Teboul L, Dear TN, Kelsey G, Peters J: Uncoupling antisense-mediated silencing and DNA methylation in the imprinted Gnas cluster. PLoS Genet. 2011, 7: e1001347-PubMed CentralPubMedGoogle Scholar
- Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, Chang HY: Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell. 2007, 129: 1311-1323.PubMed CentralPubMedGoogle Scholar
- Ng SY, Johnson R, Stanton LW: Human long non-coding RNAs promote pluripotency and neuronal differentiation by association with chromatin modifiers and transcription factors. EMBO J. 2011, 31: 522-533.PubMed CentralPubMedGoogle Scholar
- Guttman M, Rinn JL: Modular regulatory principles of large non-coding RNAs. Nature. 2012, 482: 339-346.PubMed CentralPubMedGoogle Scholar
- Wutz A: Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation. Nat Rev Genet. 2011, 12: 542-553.PubMedGoogle Scholar
- Ørom UA, Derrien T, Beringer M, Gumireddy K, Gardini A, Bussotti G, Lai F, Zytnicki M, Notredame C, Huang Q, Guigo R, Shiekhattar R: Long noncoding RNAs with enhancer-like function in human cells. Cell. 2010, 143: 46-58.PubMed CentralPubMedGoogle Scholar
- Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, Lajoie BR, Protacio A, Flynn RA, Gupta RA, Wysocka J, Lei M, Dekker J, Helms JA, Chang HY: A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 2011, 472: 120-124.PubMed CentralPubMedGoogle Scholar
- Magistri M, Faghihi MA, St Laurent G, Wahlestedt C: Regulation of chromatin structure by long noncoding RNAs: focus on natural antisense transcripts. Trends Genet. 2012, 28: 389-396.PubMed CentralPubMedGoogle Scholar
- Heo JB, Sung S: Vernalization-mediated epigenetic silencing by a long intronic noncoding RNA. Science. 2011, 331: 76-79.PubMedGoogle Scholar
- Shearwin KE, Callen BP, Egan JB: Transcriptional interference–a crash course. Trends Genet. 2005, 21: 339-345.PubMed CentralPubMedGoogle Scholar
- Palmer AC, Egan JB, Shearwin KE: Transcriptional interference by RNA polymerase pausing and dislodgement of transcription factors. Transcription. 2011, 2: 9-14.PubMed CentralPubMedGoogle Scholar
- Bird AJ, Gordon M, Eide DJ, Winge DR: Repression of ADH1 and ADH3 during zinc deficiency by Zap1-induced intergenic RNA transcripts. EMBO J. 2006, 25: 5726-5734.PubMed CentralPubMedGoogle Scholar
- Bumgarner SL, Dowell RD, Grisafi P, Gifford DK, Fink GR: Toggle involving cis-interfering noncoding RNAs controls variegated gene expression in yeast. Proc Natl Acad Sci U S A. 2009, 106: 18321-18326.PubMed CentralPubMedGoogle Scholar
- Petruk S, Sedkov Y, Riley KM, Hodgson J, Schweisguth F, Hirose S, Jaynes JB, Brock HW, Mazo A: Transcription of bxd noncoding RNAs promoted by trithorax represses Ubx in cis by transcriptional interference. Cell. 2006, 127: 1209-1221.PubMed CentralPubMedGoogle Scholar
- Gummalla M, Maeda RK, Castro Alvarez JJ, Gyurkovics H, Singari S, Edwards KA, Karch F, Bender W: abd-A regulation by the iab-8 noncoding RNA. PLoS Genet. 2012, 8: e1002720-PubMed CentralPubMedGoogle Scholar
- Latos PA, Pauler FM, Koerner MV, Şenergin HB, Hudson QJ, Stocsits RR, Allhoff W, Stricker SH, Klement RM, Warczok KE, Aumayr K, Pasierbek P, Barlow DP: Airn transcriptional overlap, but not its lncRNA products, induces imprinted Igf2r silencing. Science. 2012, 338: 1469-1472.PubMedGoogle Scholar
- MacIsaac JL, Bogutz AB, Morrissy AS, Lefebvre L: Tissue-specific alternative polyadenylation at the imprinted gene Mest regulates allelic usage at Copg2. Nucleic Acids Res. 2012, 40: 1523-1535.PubMed CentralPubMedGoogle Scholar
- Wood AJ, Schulz R, Woodfine K, Koltowska K, Beechey CV, Peters J, Bourc'his D, Oakey RJ: Regulation of alternative polyadenylation by genomic imprinting. Genes Dev. 2008, 22: 1141-1146.PubMed CentralPubMedGoogle Scholar
- Hobson DJ, Wei W, Steinmetz LM, Svejstrup JQ: RNA polymerase II collision interrupts convergent transcription. Mol Cell. 2012, 48: 365-374.PubMed CentralPubMedGoogle Scholar
- Kornberg RD, Lorch Y: Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell. 1999, 98: 285-294.PubMedGoogle Scholar
- Li B, Carey M, Workman JL: The role of chromatin during transcription. Cell. 2007, 128: 707-719.PubMedGoogle Scholar
- Weiner A, Hughes A, Yassour M, Rando OJ, Friedman N: High-resolution nucleosome mapping reveals transcription-dependent promoter packaging. Genome Res. 2010, 20: 90-100.PubMed CentralPubMedGoogle Scholar
- Hughes AL, Jin Y, Rando OJ, Struhl K: A functional evolutionary approach to identify determinants of nucleosome positioning: a unifying model for establishing the genome-wide pattern. Mol Cell. 2012, 48: 5-15.PubMed CentralPubMedGoogle Scholar
- Valouev A, Johnson SM, Boyd SD, Smith CL, Fire AZ, Sidow A: Determinants of nucleosome organization in primary human cells. Nature. 2011, 474: 516-520.PubMed CentralPubMedGoogle Scholar
- Segal E, Widom J: What controls nucleosome positions?. Trends Genet. 2009, 25: 335-343.PubMed CentralPubMedGoogle Scholar
- Radman-Livaja M, Rando OJ: Nucleosome positioning: how is it established, and why does it matter?. Dev Biol. 2010, 339: 258-266.PubMed CentralPubMedGoogle Scholar
- Martens JA, Laprade L, Winston F: Intergenic transcription is required to repress the Saccharomyces cerevisiae SER3 gene. Nature. 2004, 429: 571-574.PubMedGoogle Scholar
- Belotserkovskaya R, Oh S, Bondarenko VA, Orphanides G, Studitsky VM, Reinberg D: FACT facilitates transcription-dependent nucleosome alteration. Science. 2003, 301: 1090-1093.PubMedGoogle Scholar
- Reinberg D, Sims RJ: de FACTo nucleosome dynamics. J Biol Chem. 2006, 281: 23297-23301.PubMedGoogle Scholar
- Nourani A, Robert F, Winston F: Evidence that Spt2/Sin1, an HMG-like factor, plays roles in transcription elongation, chromatin structure, and genome stability in Saccharomyces cerevisiae. Mol Cell Biol. 2006, 26: 1496-1509.PubMed CentralPubMedGoogle Scholar
- Hainer SJ, Pruneski JA, Mitchell RD, Monteverde RM, Martens JA: Intergenic transcription causes repression by directing nucleosome assembly. Genes Dev. 2011, 25: 29-40.PubMed CentralPubMedGoogle Scholar
- Thebault P, Boutin G, Bhat W, Rufiange A, Martens J, Nourani A: Transcription regulation by the noncoding RNA SRG1 requires Spt2-dependent chromatin deposition in the wake of RNA polymerase II. Mol Cell Biol. 2011, 31: 1288-1300.PubMed CentralPubMedGoogle Scholar
- Kaplan CD, Laprade L, Winston F: Transcription elongation factors repress transcription initiation from cryptic sites. Science. 2003, 301: 1096-1099.PubMedGoogle Scholar
- Cheung V, Chua G, Batada NN, Landry CR, Michnick SW, Hughes TR, Winston F: Chromatin- and transcription-related factors repress transcription from within coding regions throughout the Saccharomyces cerevisiae genome. PLoS Biol. 2008, 6: e277-PubMed CentralPubMedGoogle Scholar
- Gallastegui E, Millan-Zambrano G, Terme JM, Chavez S, Jordan A: Chromatin reassembly factors are involved in transcriptional interference promoting HIV latency. J Virol. 2011, 85: 3187-3202.PubMed CentralPubMedGoogle Scholar
- Bannister AJ, Kouzarides T: Regulation of chromatin by histone modifications. Cell Res. 2011, 21: 381-395.PubMed CentralPubMedGoogle Scholar
- Brookes E, Pombo A: Modifications of RNA polymerase II are pivotal in regulating gene expression states. EMBO Rep. 2009, 10: 1213-1219.PubMed CentralPubMedGoogle Scholar
- Ehrensberger AH, Svejstrup JQ: Reprogramming chromatin. Crit Rev Biochem Mol Biol. 2012, 47: 464-482.PubMedGoogle Scholar
- Ng HH, Robert F, Young RA, Struhl K: Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity. Mol Cell. 2003, 11: 709-719.PubMedGoogle Scholar
- Krogan NJ, Kim M, Tong A, Golshani A, Cagney G, Canadien V, Richards DP, Beattie BK, Emili A, Boone C, Shilatifard A, Buratowski S, Greenblatt J: Methylation of histone H3 by Set2 in Saccharomyces cerevisiae is linked to transcriptional elongation by RNA polymerase II. Mol Cell Biol. 2003, 23: 4207-4218.PubMed CentralPubMedGoogle Scholar
- Schneider R, Bannister AJ, Myers FA, Thorne AW, Crane-Robinson C, Kouzarides T: Histone H3 lysine 4 methylation patterns in higher eukaryotic genes. Nat Cell Biol. 2004, 6: 73-77.PubMedGoogle Scholar
- Carrozza MJ, Li B, Florens L, Suganuma T, Swanson SK, Lee KK, Shia WJ, Anderson S, Yates J, Washburn MP, Workman JL: Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell. 2005, 123: 581-592.PubMedGoogle Scholar
- Kim T, Buratowski S: Dimethylation of H3K4 by Set1 recruits the Set3 histone deacetylase complex to 5' transcribed regions. Cell. 2009, 137: 259-272.PubMed CentralPubMedGoogle Scholar
- Keogh MC, Kurdistani SK, Morris SA, Ahn SH, Podolny V, Collins SR, Schuldiner M, Chin K, Punna T, Thompson NJ, Boone C, Emili A, Weissman JS, Hughes TR, Strahl BD, Grunstein M, Greenblatt JF, Buratowski S, Krogan NJ: Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex. Cell. 2005, 123: 593-605.PubMedGoogle Scholar
- van Werven FJ, Neuert G, Hendrick N, Lardenois A, Buratowski S, van Oudenaarden A, Primig M, Amon A: Transcription of two long noncoding RNAs mediates mating-type control of gametogenesis in budding yeast. Cell. 2012, 150: 1170-1181.PubMed CentralPubMedGoogle Scholar
- Houseley J, Rubbi L, Grunstein M, Tollervey D, Vogelauer M: A ncRNA modulates histone modification and mRNA induction in the yeast GAL gene cluster. Mol Cell. 2008, 32: 685-695.PubMedGoogle Scholar
- Kim T, Xu Z, Clauder-Munster S, Steinmetz LM, Buratowski S: Set3 HDAC mediates effects of overlapping noncoding transcription on gene induction kinetics. Cell. 2012, 150: 1158-1169.PubMed CentralPubMedGoogle Scholar
- Jones PA: Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 2012, 13: 484-492.PubMedGoogle Scholar
- Deaton AM, Bird A: CpG islands and the regulation of transcription. Genes Dev. 2011, 25: 1010-1022.PubMed CentralPubMedGoogle Scholar
- Ooi SK, O'Donnell AH, Bestor TH: Mammalian cytosine methylation at a glance. J Cell Sci. 2009, 122: 2787-2791.PubMed CentralPubMedGoogle Scholar
- Ooi SK, Qiu C, Bernstein E, Li K, Jia D, Yang Z, Erdjument-Bromage H, Tempst P, Lin SP, Allis CD, Cheng X, Bestor TH: DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature. 2007, 448: 714-717.PubMed CentralPubMedGoogle Scholar
- Tufarelli C, Stanley JA, Garrick D, Sharpe JA, Ayyub H, Wood WG, Higgs DR: Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nat Genet. 2003, 34: 157-165.PubMedGoogle Scholar
- Ligtenberg MJ, Kuiper RP, Chan TL, Goossens M, Hebeda KM, Voorendt M, Lee TY, Bodmer D, Hoenselaar E, Hendriks-Cornelissen SJ, Tsui WY, Kong CK, Brunner HG, van Kessel AG, Yuen ST, van Krieken JH, Leung SY, Hoogerbrugge N: Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet. 2009, 41: 112-117.PubMedGoogle Scholar
- Santoro F, Barlow DP: Developmental control of imprinted expression by macro non-coding RNAs. Semin Cell Dev Biol. 2011, 22: 328-335.PubMedGoogle Scholar
- Santoro F, Mayer D, Klement RM, Warczok KE, Stukalov A, Barlow DP, Pauler FM: Imprinted Igf2r silencing depends on continuous Airn lncRNA expression and is not restricted to a developmental window. Development. 2013, 140: 1184-1195.PubMedGoogle Scholar
- Pauler FM, Barlow DP, Hudson QJ: Mechanisms of long range silencing by imprinted macro non-coding RNAs. Curr Opin Genet Dev. 2012, 22: 283-289.PubMed CentralPubMedGoogle Scholar
- Pauler FM, Koerner MV, Barlow DP: Silencing by imprinted noncoding RNAs: is transcription the answer?. Trends Genet. 2007, 23: 284-292.PubMed CentralPubMedGoogle Scholar
- Barlow DP: Genomic imprinting: a mammalian epigenetic discovery model. Annu Rev Genet. 2011, 45: 379-403.PubMedGoogle Scholar
- Koerner MV, Pauler FM, Huang R, Barlow DP: The function of non-coding RNAs in genomic imprinting. Development. 2009, 136: 1771-1783.PubMed CentralPubMedGoogle Scholar
- Wang ZQ, Fung MR, Barlow DP, Wagner EF: Regulation of embryonic growth and lysosomal targeting by the imprinted Igf2/Mpr gene. Nature. 1994, 372: 464-467.PubMedGoogle Scholar
- Pauler FM, Stricker SH, Warczok KE, Barlow DP: Long-range DNase I hypersensitivity mapping reveals the imprinted Igf2r and Air promoters share cis-regulatory elements. Genome Res. 2005, 15: 1379-1387.PubMed CentralPubMedGoogle Scholar
- Stoger R, Kubicka P, Liu CG, Kafri T, Razin A, Cedar H, Barlow DP: Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal. Cell. 1993, 73: 61-71.PubMedGoogle Scholar
- Racanelli AC, Turner FB, Xie LY, Taylor SM, Moran RG: A mouse gene that coordinates epigenetic controls and transcriptional interference to achieve tissue-specific expression. Mol Cell Biol. 2008, 28: 836-848.PubMed CentralPubMedGoogle Scholar
- Palmer AC, Ahlgren-Berg A, Egan JB, Dodd IB, Shearwin KE: Potent transcriptional interference by pausing of RNA polymerases over a downstream promoter. Mol Cell. 2009, 34: 545-555.PubMed CentralPubMedGoogle Scholar
- Adelman K, Lis JT: Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat Rev Genet. 2012, 13: 720-731.PubMed CentralPubMedGoogle Scholar
- Levine M: Paused RNA polymerase II as a developmental checkpoint. Cell. 2011, 145: 502-511.PubMed CentralPubMedGoogle Scholar
- Nagano T, Mitchell JA, Sanz LA, Pauler FM, Ferguson-Smith AC, Feil R, Fraser P: The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science. 2008, 322: 1717-1720.PubMedGoogle Scholar
- Mager J, Montgomery ND, de Villena FP, Magnuson T: Genome imprinting regulated by the mouse Polycomb group protein Eed. Nat Genet. 2003, 33: 502-507.PubMedGoogle Scholar
- Terranova R, Yokobayashi S, Stadler MB, Otte AP, van Lohuizen M, Orkin SH, Peters AH: Polycomb group proteins Ezh2 and Rnf2 direct genomic contraction and imprinted repression in early mouse embryos. Dev Cell. 2008, 15: 668-679.PubMedGoogle Scholar
- Korostowski L, Sedlak N, Engel N: The Kcnq1ot1 long non-coding RNA affects chromatin conformation and expression of Kcnq1, but does not regulate its imprinting in the developing heart. PLoS Genet. 2012, 8: e1002956-PubMed CentralPubMedGoogle Scholar
- Visel A, Rubin EM, Pennacchio LA: Genomic views of distant-acting enhancers. Nature. 2009, 461: 199-205.PubMed CentralPubMedGoogle Scholar
- Ong CT, Corces VG: Enhancers: emerging roles in cell fate specification. EMBO Rep. 2012, 13: 423-430.PubMed CentralPubMedGoogle Scholar
- Kim TK, Hemberg M, Gray JM, Costa AM, Bear DM, Wu J, Harmin DA, Laptewicz M, Barbara-Haley K, Kuersten S, Markenscoff-Papadimitriou E, Kuhl D, Bito H, Worley PF, Kreiman G, Greenberg ME: Widespread transcription at neuronal activity-regulated enhancers. Nature. 2010, 465: 182-187.PubMed CentralPubMedGoogle Scholar
- Schatz DG, Swanson PC: V(D)J recombination: mechanisms of initiation. Annu Rev Genet. 2011, 45: 167-202.PubMedGoogle Scholar
- Bolland DJ, Wood AL, Afshar R, Featherstone K, Oltz EM, Corcoran AE: Antisense intergenic transcription precedes Igh D-to-J recombination and is controlled by the intronic enhancer Emu. Mol Cell Biol. 2007, 27: 5523-5533.PubMed CentralPubMedGoogle Scholar
- Giallourakis CC, Franklin A, Guo C, Cheng HL, Yoon HS, Gallagher M, Perlot T, Andzelm M, Murphy AJ, Macdonald LE, Yancopoulos GD, Alt FW: Elements between the IgH variable (V) and diversity (D) clusters influence antisense transcription and lineage-specific V(D)J recombination. Proc Natl Acad Sci U S A. 2010, 107: 22207-22212.PubMed CentralPubMedGoogle Scholar
- Abarrategui I, Krangel MS: Noncoding transcription controls downstream promoters to regulate T-cell receptor alpha recombination. EMBO J. 2007, 26: 4380-4390.PubMed CentralPubMedGoogle Scholar
- Ashe HL, Monks J, Wijgerde M, Fraser P, Proudfoot NJ: Intergenic transcription and transinduction of the human beta-globin locus. Genes Dev. 1997, 11: 2494-2509.PubMed CentralPubMedGoogle Scholar
- Gribnau J, Diderich K, Pruzina S, Calzolari R, Fraser P: Intergenic transcription and developmental remodeling of chromatin subdomains in the human beta-globin locus. Mol Cell. 2000, 5: 377-386.PubMedGoogle Scholar
- Cumberledge S, Zaratzian A, Sakonju S: Characterization of two RNAs transcribed from the cis-regulatory region of the abd-A domain within the Drosophila bithorax complex. Proc Natl Acad Sci U S A. 1990, 87: 3259-3263.PubMed CentralPubMedGoogle Scholar
- Beisel C, Paro R: Silencing chromatin: comparing modes and mechanisms. Nat Rev Genet. 2011, 12: 123-135.PubMedGoogle Scholar
- Schmitt S, Prestel M, Paro R: Intergenic transcription through a polycomb group response element counteracts silencing. Genes Dev. 2005, 19: 697-708.PubMed CentralPubMedGoogle Scholar
- Sessa L, Breiling A, Lavorgna G, Silvestri L, Casari G, Orlando V: Noncoding RNA synthesis and loss of Polycomb group repression accompanies the colinear activation of the human HOXA cluster. RNA. 2007, 13: 223-239.PubMed CentralPubMedGoogle Scholar
- Kanhere A, Viiri K, Araújo CC, Rasaiyaah J, Bouwman RD, Whyte WA, Pereira CF, Brookes E, Walker K, Bell GW, Pombo A, Fisher AG, Young RA, Jenner RG: Short RNAs are transcribed from repressed polycomb target genes and interact with polycomb repressive complex-2. Mol Cell. 2010, 38: 675-688.PubMed CentralPubMedGoogle Scholar
- Hekimoglu-Balkan B, Aszodi A, Heinen R, Jaritz M, Ringrose L: Intergenic Polycomb target sites are dynamically marked by non-coding transcription during lineage commitment. RNA Biol. 9: 314-325.Google Scholar
- Uhler JP, Hertel C, Svejstrup JQ: A role for noncoding transcription in activation of the yeast PHO5 gene. Proc Natl Acad Sci U S A. 2007, 104: 8011-8016.PubMed CentralPubMedGoogle Scholar
- Neil H, Malabat C, d'Aubenton-Carafa Y, Xu Z, Steinmetz LM, Jacquier A: Widespread bidirectional promoters are the major source of cryptic transcripts in yeast. Nature. 2009, 457: 1038-1042.PubMedGoogle Scholar
- Seila AC, Calabrese JM, Levine SS, Yeo GW, Rahl PB, Flynn RA, Young RA, Sharp PA: Divergent transcription from active promoters. Science. 2008, 322: 1849-1851.PubMed CentralPubMedGoogle Scholar
- Brosius J: Waste not, want not–transcript excess in multicellular eukaryotes. Trends Genet. 2005, 21: 287-288.PubMedGoogle Scholar
- Kowalczyk MS, Higgs DR, Gingeras TR: Molecular biology: RNA discrimination. Nature. 2012, 482: 310-311.PubMedGoogle Scholar
- Wang GZ, Lercher MJ, Hurst LD: Transcriptional coupling of neighboring genes and gene expression noise: evidence that gene orientation and noncoding transcripts are modulators of noise. Genome Biol Evol. 2011, 3: 320-331.PubMedGoogle Scholar
- Ulitsky I, Shkumatava A, Jan CH, Sive H, Bartel DP: Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. Cell. 2011, 147: 1537-1550.PubMed CentralPubMedGoogle Scholar
- Zeng Y, Cullen BR: RNA interference in human cells is restricted to the cytoplasm. RNA. 2002, 8: 855-860.PubMed CentralPubMedGoogle Scholar
- Ohrt T, Muetze J, Svoboda P, Schwille P: Intracellular localization and routing of miRNA and RNAi pathway components. Curr Top Med Chem. 2012, 12: 79-88.PubMedGoogle Scholar
- Ideue T, Hino K, Kitao S, Yokoi T, Hirose T: Efficient oligonucleotide-mediated degradation of nuclear noncoding RNAs in mammalian cultured cells. RNA. 2009, 15: 1578-1587.PubMed CentralPubMedGoogle Scholar
- Tse MT: Antisense therapeutics: Nuclear RNA more susceptible to knockdown. Nat Rev Drug Discov. 2012, 11: 674-PubMedGoogle Scholar
- Zhang B, Arun G, Mao YS, Lazar Z, Hung G, Bhattacharjee G, Xiao X, Booth CJ, Wu J, Zhang C, Spector DL: The lncRNA Malat1 is dispensable for mouse development but its transcription plays a cis-regulatory role in the adult. Cell Rep. 2012, 2: 111-123.PubMed CentralPubMedGoogle Scholar
- Nakagawa S, Naganuma T, Shioi G, Hirose T: Paraspeckles are subpopulation-specific nuclear bodies that are not essential in mice. J Cell Biol. 193: 31-39.Google Scholar
- Eißmann M, Gutschner T, Hämmerle M, Günther S, Caudron-Herger M, Groß M, Schirmacher P, Rippe K, Braun T, Zörnig M, Diederichs S: Loss of the abundant nuclear non-coding RNA MALAT1 is compatible with life and development. RNA Biol. 2012, 9: 1076-1087.PubMed CentralPubMedGoogle Scholar
- Nakagawa S, Ip JY, Shioi G, Tripathi V, Zong X, Hirose T, Prasanth KV: Malat1 is not an essential component of nuclear speckles in mice. RNA. 2012, 18: 1487-1499.PubMed CentralPubMedGoogle Scholar
- Schorderet P, Duboule D: Structural and functional differences in the long non-coding RNA hotair in mouse and human. PLoS Genet. 2011, 7: e1002071-PubMed CentralPubMedGoogle Scholar
- Guenzl PM, Barlow DP: Macro lncRNAs: A new layer of cis-regulatory information in the mammalian genome. RNA Biol. 2012, 9: 731-741.PubMedGoogle Scholar
- Carette JE, Guimaraes CP, Wuethrich I, Blomen VA, Varadarajan M, Sun C, Bell G, Yuan B, Muellner MK, Nijman SM, Ploegh HL, Brummelkamp TR: Global gene disruption in human cells to assign genes to phenotypes by deep sequencing. Nat Biotechnol. 2011, 29: 542-546.PubMed CentralPubMedGoogle Scholar
- Wirt SE, Porteus MH: Development of nuclease-mediated site-specific genome modification. Curr Opin Immunol. 2012, 24: 609-616.PubMedGoogle Scholar
- Mali P, Yang L, Esvelt KM, Aach J, Guell M, Dicarlo JE, Norville JE, Church GM: RNA-Guided Human Genome Engineering via Cas9. Science. 2013, 339: 823-826.PubMed CentralPubMedGoogle Scholar
- Latos PA, Stricker SH, Steenpass L, Pauler FM, Huang R, Senergin BH, Regha K, Koerner MV, Warczok KE, Unger C, Barlow DP: An in vitro ES cell imprinting model shows that imprinted expression of the Igf2r gene arises from an allele-specific expression bias. Development. 2009, 136: 437-448.PubMed CentralPubMedGoogle Scholar
- Kohama C, Kato H, Numata K, Hirose M, Takemasa T, Ogura A, Kiyosawa H: ES cell differentiation system recapitulates the establishment of imprinted gene expression in a cell-type-specific manner. Hum Mol Genet. 2012, 21: 1391-1401.PubMedGoogle Scholar
- Rosenbloom KR, Sloan CA, Malladi VS, Dreszer TR, Learned K, Kirkup VM, Wong MC, Maddren M, Fang R, Heitner SG, Lee BT, Barber GP, Harte RA, Diekhans M, Long JC, Wilder SP, Zweig AS, Karolchik D, Kuhn RM, Haussler D, Kent WJ: ENCODE Data in the UCSC Genome Browser: year 5 update. Nucleic Acids Res. 2013, 41: D56-63.PubMed CentralPubMedGoogle Scholar
- Loven J, Orlando DA, Sigova AA, Lin CY, Rahl PB, Burge CB, Levens DL, Lee TI, Young RA: Revisiting global gene expression analysis. Cell. 2012, 151: 476-482.PubMed CentralPubMedGoogle Scholar
- Clark MB, Mattick JS: Long noncoding RNAs in cell biology. Semin Cell Dev Biol. 2011, 22: 366-376.PubMedGoogle Scholar
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