Recent years have seen the increasing understanding of the crucial role of RNA in the functioning of the eukaryotic genome. These discoveries, fueled by the achievements of the FANTOM, and later GENCODE and ENCODE consortia, led to the recognition of the important regulatory roles of natural antisense transcripts (NATs) arising from what was previously thought to be ‘junk DNA’. Roughly defined as non-coding regulatory RNA transcribed from the opposite strand of a coding gene locus, NATs are proving to be a heterogeneous group with high potential for therapeutic application. Here, we attempt to summarize the rapidly growing knowledge about this important non-coding RNA subclass.

INTRODUCTION

Although DNA and RNA were first discovered at the same time, it took >150 years for the RNA to emerge from the shadow of its longer sibling. Only now the full structural and regulatory role of RNA is becoming apparent, leading to the emerging understanding of the eukaryotic genome as an RNA machine (1). Efforts of multiple scientists, fueled by the achievements of the FANTOM, and later GENCODE and ENCODE consortia, expanded the scope of RNA functions from a single role of carrying information from DNA to ribosomes to a wide spectrum of regulatory and structural roles in gene expression, genomic imprinting and chromatin rearrangement (26). The journey of the non-coding RNA (ncRNA) from ‘genomic junk’ to biological prominence has arguably been long and tortuous (1,7).

As the identity and functions of non-coding transcripts are still in the early stages of discovery, so is their classification. A commonly used grouping based mostly on the order of discovery, divides non-coding transcripts into rRNA, tRNAs, snRNAs, snoRNAs, short (miRNA, piRNA) and long non-coding RNAs (lncRNA). However, as structures and functions of multiple non-coding transcripts become better characterized, it is becoming clear that the classification based on this grouping is not very useful. In fact, it might even impede progress by artificially separating similar entities into different classes and encouraging scientists to overlook, for example, the dual lncRNA and miRNA aspects of some ncRNAs. Even the division into coding and ncRNAs is gradually becoming less obvious, as cases are discovered where a coding gene mRNA functions as a regulatory molecule in its own right or an ncRNA is found to produce a protein (8,9). The current neat picture of the RNA world could be threatened even further by the recently proposed model where transcripts are generated constantly at low levels from different points of the genome to allow transcription surveillance machinery to sample the local context and engage in appropriate action.

Despite the lack of comprehensive classification, we have to limit our review to a subgroup of RNAs due to space constraints. We will focus on natural antisense transcripts (NATs) which are relatively less studied than ribosomal/tRNAs, short ncRNAs and even another subgroup of lncRNA, long-intergenic non-coding RNAs (lincRNAs) (10,11). Furthermore, due to their highly gene locus-specific effects, NATs may provide a unique entry point for therapeutic intervention in targeted gene upregulation (12). For the purpose of this review, we will define NATs as ncRNAs transcribed from the opposite strand of a coding gene and capable of regulating the expression of their sense gene pair or of several related genes. As will be described, this group is highly heterogeneous. NATs may originate from all parts of a given protein coding locus. The effect of NATs on their partner coding genes could include suppression, activation or homeostatic adjustment, and the mechanisms may be as different as recruitment of epigenetic modifier enzymes, ncRNA/mRNA pairing or stabilization of long-range chromosomal interactions. Below we will review examples of these cases.

NATS: STRUCTURAL AND FUNCTIONAL DIVERSITY

NAT sequences

For the NAT subclass as a whole, no clear sequence motifs have yet been identified. Furthermore, NAT sequences are poorly conserved among species (13). It has been proposed that it is secondary and/or tertiary structures that are evolutionally conserved and are essential for NAT and other lncRNA functions (14). It is also possible that closer homologies will emerge when known RNA transcripts are grouped in a different way. For example, when a group of 141 intronic regions and 74 intergenic transcripts obtained by deep sequencing of intronic and intergenic chromatin-associated RNAs was analyzed, it showed significant conservation across 44 species of mammals (15).

Interestingly, common NAT sequences can be contributed by the transposable elements. Some of the active human endogenous retroviruses (HERVs) are transcribed from the coding gene loci in antisense direction and regulate these genes in a discordant fashion, thus qualifying as NATs (e.g. HERV-Ec1 and HERV-Ec6 proviruses located in PLA2G4A and RNGTT genes) (16). HERV promoters frequently originate expression of new isoforms of both coding and non-coding genes (17,18). Some NATs contain short interspersed nuclear element B2 (SINEB2), for example antisense Uchl1 which includes a part overlapping a 5′ sequence of Uchl1 and an embedded inverted SINEB2 (19). Tspo NAT was created by extension of the SINEB2 transcript to exon 3 of the Tspo gene (20).

Some of the pseudogenes, frequently generated through inverted gene duplications, may give rise to lncRNA transcripts with regulatory functions (21).

The search for common NAT motifs is further complicated by the fact that RNAs can combine coding and non-coding roles. For example, steroid receptor RNA activator thought to be non-coding was found to produce a highly conserved small protein (9).

Localization of NATs relative to coding gene sequences

Known NATs overlap introns, exons, promoters, enhancers, UTRs and flanking sequences of the partner coding genes, in all combinations. Head-to-head, tail-to-tail and fully overlapped with coding gene NAT configurations have also been observed.

Several groups have attempted associating relative position of lncRNA with its function, as deduced from correlation in temporal profiles and expression levels of their partner protein-coding genes. Batagov et al. (22) found weak positive correlation in expression for coding/non-coding gene pairs at bidirectional promoters and for sense–antisense transcript pairs during a 120-h time course of differentiation of human neuroblastoma SH-SY5Y cells into neurons after treatment with retinoic acid. In contrast, lncRNAs located in the introns and downstream of the protein-coding genes showed negative correlation. Using directional RNA-seq data from of mouse and chimpanzee tissues, Uesaka et al. (23) have noted that loci with tissue-specific expression frequently contain lncRNAs overlapping the coding gene promoter (termed promoter-associated ncRNAs or pancRNAs), whereas constitutively expressed genes usually did not have pancRNAs. Furthermore, expression of pancRNAs and their coding partners was positively correlated.

Head-to-head configuration of coding/non-coding gene pairs has been closely investigated in recent years (24,25). It has been shown that a significant fraction of the transcription start sites of protein-coding genes may be generating bidirectional transcription (23). More than 60% of the lncRNA transcripts in human and murine embryonic stem cells (ESCs) originate from bidirectional promoters (26). It has been proposed that transcription of the ncRNA from these sites may be suppressed by a gene-loop configuration formed by Ssu72 protein, which interacts with both the promoter and terminator of the active protein-coding genes and restricts divergent transcription of ncRNAs (27).

A subset of enhancers has been shown to produce lncRNAs termed eRNAs, which may form a separate NAT subgroup. Such eRNA-producing enhancer at Nanog locus exhibited decreased DNA methylation, elevated levels of the active mark H3K27Ac and DNA hydroxylase Tet1. Binding of Sall4 and Tet family proteins was necessary for eRNA transcription at this locus (28).

Mechanisms of NAT-mediated regulation

Multiple mechanisms have been proposed for NAT-dependent regulation of coding protein expression. It is likely that the mechanism of action would constitute the most meaningful basis for NAT classification. However, the currently available data are too sketchy and only a preliminary grouping by mechanism of action type can be suggested. It is possible that as more information becomes available more NATs will be found to participate simultaneously in several types of regulation described below.

Interaction with protein complexes: decoy, scaffolding and tethering mechanisms

Different authors describe lncRNAs interacting with protein complexes as decoys, scaffolds or tethers/guides. Typically, decoys interact with one partner, whereas scaffolds and tethers/guides bridge groups of targets. In practice, however, it is hard to draw a clear line between these three groups. Both tethers and scaffolds can display some aspects of decoy mechanism. The overlap is even bigger between scaffolding and tethering groups. Below, we will review some of the cases keeping the decoy, scaffold or tether/guide description given by the authors for convenience.

The decoy mechanism mostly involves different lncRNAs competing for the binding sites with other molecules (Fig. 1). A classic case of decoy mechanism has been described by Huang et al. (29). hnRNP I enhances the translation of p27 (Kip1) through interaction with its 5′-untranslated region. lncRNA UCA1 displaces p27 RNA from the hnRNP I complex which leads to a decrease in p27 protein level. An interesting variation on the decoy mechanism is described for lncRNA cardiac hypertrophy-related factor that downregulates miR-489 expression levels by directly binding to and sequestering miR-489 in a model of AngII-induced cardiac hypertrophy (30).

Figure 1.

Proposed mechanisms of NAT-mediated regulation. (A) Interaction with protein complexes: decoy mechanism. NAT binds to a protein complex, which either prevents RNApol binding to the coding gene's promoter and thus inhibits transcription or interferes with mRNA translation (not shown) (29,30). (B) Interaction with protein complexes: tethering mechanism. NAT is transcribed from the opposite strand of the protein-coding locus. The NAT-mediated tethering can occur by the nascent NAT at the time of NAT transcription or after NAT transcription has been completed, by pairing with DNA or nascent mRNA sequences. NAT then binds a protein complex (e.g. PRC2) thus tethering it to the coding gene locus, and/or scaffolding several proteins at the promoter site. PRC2 catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3), which is recognized by PRC1. PRC1 then catalyzes the monoubiquitylation of histone H2A, which contributes to chromatin compaction and repression of the target locus (2,31). (C) Generation of endogenous siRNAs and miRNA. NAT forms internal hairpins or duplexes with mRNA in the areas of homology. The double-stranded RNA stretches are trimmed by Dicer to form short RNA duplexes, which are then bound by the RISC complex and used as a template for recognition of mRNA. Captured mRNA is then cleaved by the RISC complex, reducing protein expression (32,33).

Figure 1.

Proposed mechanisms of NAT-mediated regulation. (A) Interaction with protein complexes: decoy mechanism. NAT binds to a protein complex, which either prevents RNApol binding to the coding gene's promoter and thus inhibits transcription or interferes with mRNA translation (not shown) (29,30). (B) Interaction with protein complexes: tethering mechanism. NAT is transcribed from the opposite strand of the protein-coding locus. The NAT-mediated tethering can occur by the nascent NAT at the time of NAT transcription or after NAT transcription has been completed, by pairing with DNA or nascent mRNA sequences. NAT then binds a protein complex (e.g. PRC2) thus tethering it to the coding gene locus, and/or scaffolding several proteins at the promoter site. PRC2 catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3), which is recognized by PRC1. PRC1 then catalyzes the monoubiquitylation of histone H2A, which contributes to chromatin compaction and repression of the target locus (2,31). (C) Generation of endogenous siRNAs and miRNA. NAT forms internal hairpins or duplexes with mRNA in the areas of homology. The double-stranded RNA stretches are trimmed by Dicer to form short RNA duplexes, which are then bound by the RISC complex and used as a template for recognition of mRNA. Captured mRNA is then cleaved by the RISC complex, reducing protein expression (32,33).

Tethering of epigenetic modulators has been first described for lncRNAs in the context of imprinting. These interactions for the most part involve polycomb group protein complexes PRC1 (polycomb repressive complex 1) and PRC2 tethering to defined gene loci. This group of interactions has recently been expanded to include developmentally and environmentally driven epigenetic modification of the non-imprinted loci (reviewed in 34,35) (Fig. 1). PRC2 catalyzes the di- and trimethylation of histone H3 at lysine 27 (H3K27me2 or H3K27me3), which is recognized by PRC1. PRC1 then catalyzes the monoubiquitylation of histone H2A, which contributes to chromatin compaction and repression of the target locus. The mechanism of PRC2 recruitment is currently not completely understood and is likely locus or environment dependent. Factors involved in this process may include CpG-rich domains and other sequence features of the promoters, DNA-binding proteins and IncRNA. lncRNA may be used to tether/guide/direct the complex to particular target genes through both base pairing to DNA and secondary–tertiary structure-driven protein binding. The tethering can occur by the nascent NAT at the time of NAT transcription or after NAT transcription has been completed, by pairing with DNA or mRNA sequences. There are several possible configurations for the pairing, including base pairing between the NAT and ssDNA, formation of a RNA–DNA–DNA triplex or via RNA–RNA hybrids of NATs with a nascent partner mRNA. It is possible that tethering requires participation of other protein factors because comparing human PRC2 binding to its known target lncRNAs with PRC2 binding to irrelevant transcripts, the binding constants were found to be similar in ciliates and bacteria (36). JARID2 could be one of the proteins that facilitates PRC2/lncRNA interaction, at least at imprinted loci involved in differentiation, including the Dlk1-Dio3 locus (37).

Interestingly, in mouse ESCs, PRC2 is found at both active and inactive promoters, but the H3K27me3 mark is not observed at active gene loci. Using in vivo RNA–protein cross linking, it was determined that EZH2, the catalytic subunit of PRC2, directly binds the 5′ region of nascent coding and ncRNAs at active promoters. EZH2 binding may contribute to decreased H3K27me3 deposition at these sites through the decoy mechanism (38). PRC2 also binds widely to enhancers, but H3K27me3 is only deposited at sites depleted for activating promoter motifs and enriched for motifs of developmental factors. These sequences represent blastula-stage DNA methylation-free domains that are conserved between humans, frogs and fish (39). The role of eRNAs in this process remains to be investigated.

Involvement of lncRNA in PRC2 recruitment, at least in the context of imprinting, has recently been questioned based on microarray-based epigenomic mapping and super-resolution 3D structured illumination microscopy data. Spatial separation and absence of colocalization of Xist and PRC2 was observed in the mouse ES cell line carrying an inducible Xist transgene located on chromosome 17 and in normal XX somatic cells (40).

Multiple authors have reported changes in other epigenetic DNA and chromatin marks including methylation and demethylation of H3K4, H3K9, acetylation and deacetylation of histone H3 involving multiple enzymes and epigenetic complexes, such as methyltransferases G9a, GLP and HDACs (Table 1). These alternative epigenetic modifications are likely induced by changes in NAT levels and activity.

Table 1.

Localization and mechanisms of action of known NATs

Coding gene symbol Name used in reference NAT name NAT localization relative to coding gene Effect on coding gene expression Mechanism Therapeutic relevance Model Methods Ref. 
ADAM12 ADAM12 Inter genic10 Intergenic, overlaps 3′ end of ADAM12 Concordant NAT knockdown decreases H3K4me2 in the promoter region  Human fibroblast cells Deep sequencing, ChRIP (15
APOA1 APOA1 APOA1 NAT Overlaps coding gene cluster Discordant NAT recruits LSD1 and SUZ12, affects epigenetic marks at the three promoters APOA1 cluster is involved in cardiovascular disease Human and monkey cell lines and primary hepatocytes, monkeys ChIP, real-time PCR (41
APOA4 APOA4 APOA1 NAT Overlaps coding gene cluster Discordant NAT recruits LSD1 and SUZ12, affects epigenetic marks at the three promoters APOA1 cluster is involved in cardiovascular disease Human cell lines ChIP, real-time PCR (41
APOC3 APOC3 APOA1 NAT Overlaps coding gene cluster Discordant NAT recruits LSD1 and SUZ12, affects epigenetic marks at the three promoters APOA1 cluster is involved in cardiovascular disease Human cell lines ChIP, real-time PCR (41
BACE1 BACE1 BACE1-AS Overlaps coding gene Concordant NAT masks binding site for miR-485-5p BACE1-AS is upregulated in AD brains and is involved in regulation of Aβ 1–42 production APP transgenic mice, N2a and HEK293T C3 cells, human and mouse tissues, AD brains Knockdown, overexpression, mutation analysis, DiscoveRx (4244
BDNF BDNF BDNF-AS Overlaps coding gene Discordant NAT depletion reduced H3K27met3 and Ezh2 binding, but not H3K4met3 and H3K36met3 BDNF regulates neuronal outgrowth and differentiation Human and mouse cell lines, mice, cultured human neurons, glia, mouse neurospheres Knockdown in vivo and in vitro, ChIP, IHC (31
CDKN2B p15 (INK4B) ANRIL Overlaps coding gene Discordant? NAT is required for the recruitment of PRC2 and SUZ12 binding to p15(INK4B) INK4B is activated by carcinogens to stop cell propagation Human cell lines Knockdown (45
CDKN2B p15 p15AS Overlaps coding gene Discordant? NAT mediates CDKN2B repression in cis and in trans via heterochromatin formation, not DNA methylation; repression continued after NAT expression was turned off; dicer independent p15 is implicated in leukemia Mouse ESCs, leukemic leukocytes, human cell lines Expression profiling, overexpression (46
DHRS4, DHRS4L2, DHRS4L1 DHRS4, DHRS4L2, DHRS4L1 AS1DHRS4 Antisense in intron 1 of DHRS4 Discordant for all three genes NAT pairs with ongoing sense transcripts; mediates H3 deacetylation and H3K4 demethylation of DHRS4, interacts with G9a and EZH2 in DHRS4L2 and DHRS4L1 promoters DHRS4 is important for metabolism of organic compounds Normal human hepatic (HL7702) and hepatocellular carcinoma (HepG2) cells siRNA, RNA-ChIP (47
DLX1 Dlx1 Dlx1as Overlaps coding gene Discordant?   Embryonic mouse brain qPCR, ISH (48
DLX6 DLX6 DLX6-AS/Evf2 Head to head Discordant NAT recruits DLX and MECP2 to regulatory elements in intergenic region Evf2 mouse mutants had reduced synaptic inhibition Developing mouse brain, Evf2 loss-of-function mice Evf2 electroporation into brains, qChIP-PCR (49
EPH1B EPH1B EPH1B-AS Overlaps coding gene Discordant  EPHB1 is important in brain development and function Human cells Knockdown (31
FOXG1 FOXG1 FOXG1-AS Promoter Concordant?   SH-SY5Y, normal and autistic brains Expression profiling (50
GCCR GR Gas5 Overlaps coding gene  Gas5 bound to DNA-binding domain of GCCR through its hairpin #5 without altering the abundance of GCCR target genes Gas5 sensitized cells to apoptosis HeLa cells Yeast two-hybrid screen, GR-binding defective Gas5 mutant, ChiP, overexpression, mutation analysis (51
GDNF GDNF GDNF-AS Overlaps coding gene Discordant  EPHB1 is important in brain development and function Human cells Knockdown (31
HIF1A HIF1 alpha aHIF Complementary to the 3′ UTR Discordant?  NAT is overexpressed in non-papillary kidney cancer Renal carcinomas, normal lymphocyte cell line Ribonuclease protection, expression profiling (52
HRAS p21 p21 antisense Bidirectional transcription Discordant Ago-2 is required for NAT effect; loss of NAT correlates with loss of H3K27me3 at the p21 promoter  MCF-7 cells Nuclear run on analysis, ChIP (53
IL1A IL-1a Anti-IL-1a/AK042010 Overlaps coding gene Concordant?  NAT is involved in regulation of cytokine production Mouse macrophage cell line and primary macrophages Overexpression, ChIP, expression profiling (54
IL1B IL-1β Anti-IL-1β/ AK076405 Head to head, overlaps 5′ and promoter Discordant NAT inhibited IL1B at transcriptional level NAT is involved in regulation of cytokine production Mouse macrophage cell line and primary macrophages Overexpression, ChIP, expression profiling (54
IL4I1 IL-4i1 Anti-IL-4i1/ AK087754 Overlaps coding gene Concordant?  NAT is involved in regulation of cytokine production Mouse macrophage cell line and primary macrophages Overexpression, ChIP, expression profiling (54
KCNMB4 Kcnmb4 panc Kcnmb4 Bidirectional head to head Concordant   Mouse and chimpanzee tissue samples Directional RNA-seq, RT-PCR, knockdown (23
MSTN Myostatin Mstn promoter-associated RNA Promoter Concordant NAT knockdown increases H3K9me2, but not H3K27me3 at the Mstn promoter; histone deacetylase dependent Mstn negatively regulates muscle mass Differentiated mouse muscle cell lines and myoblasts with dystrophin mutation Knockdown, expression profiling (55
MYH Myosin heavy chain (MHC) bII NAT NAT starts in IIb-Neo intergenic region and overlaps IIb MHC Discordant  bII NAT is regulated during postnatal development and in response to hypothyroidism Developing rat muscle Expression profiling (56
MYH1 IIx MHC aII NAT NAT begins in the IIa–IIx intergenic region, overlaps IIa MHC Concordant?  NAT is involved in slow to fast MHC transformation Rat muscle after spinal cord isolation Expression profiling (57
MYH1 IIx MHC xII NAT Shares bidirectional promoter with IIb MHC, overlaps IIx Discordant?  Shift from IIb to IIx expression occurs after exercise Rat tissues Expression profiling (58
MYH2 IIa MHC aII NAT NAT begins in the IIa-IIx intergenic region, overlaps IIa Discordant?  NAT is involved in slow to fast MHC transformation Rat muscle after spinal cord isolation Expression profiling (57
MYH3 Neo MHC bII NAT Begins in IIb-Neo intergenic region and overlaps IIb Concordant?  NAT regulates transition between neo and IIb MHC Normal and thyroid-deficient rat neonates treated with PTU Expression profiling (56
MYH4 IIb MHC bII NAT Starts in IIb-Neo intergenic region and overlaps IIb Discordant?  NAT regulates transition between neo and IIb MHC Normal and PTU-treated rat neonates Expression profiling (56
NFKB1 p105 Anti-p105/AK090099 Overlaps coding gene Concordant?  NAT is involved in regulation of cytokine production Mouse macrophage cell line and LPS-activated primary macrophages Expression profiling (54
NFKB2 p100 Anti-p100/ AK029443 Head to head, overlaps the 5′ region and promoter Concordant?  NAT is involved in regulation of cytokine production Mouse macrophage cell line and LPS-activated primary macrophages Overexpression, expression profiling (54
NIPBL NIPBL NIPBL-AS Promoter  NAT localized to nucleoplasm or chromatin  SH-SY5Y, normal and autistic brains Expression profiling (50
NOS2A iNOS iNOS asRNA 3′UTR of rat and mouse iNOS Concordant NAT stabilizes iNOS mRNA Reducing iNOS mRNA levels is needed in inflammatory diseases and cancers Primary hepatocytes from LPS-treated rats; IL-1β-treated hepatocytes; human tumors Knockdown (59
PACSIN1 Pacsin1 panc Pacsin1 Bidirectional transcription Concordant   Mouse and chimpanzee tissue samples RNA-seq, knockdown (23
PINK1 PINK1 naPINK1 Overlaps coding gene Concordant?  PINK1 mutations are implicated in early-onset Parkinson's Neuronal cell lines Knockdown (60
PLA2G4A PLA2G4A HERV-Ec1 Between exons 7 and 8, in antisense orientation Discordant, mutual  NAT is downregulated in urothelial carcinoma Human tumors and urothelial cell line (UROtsa) Expression profiling, knockdown (16
PQBP1 PQBP1 PQBP1-AS Overlaps exons and promoter Discordant?   SH-SY5Y, normal and autistic brains Expression profiling (50
PTCHD1 PTCHD1 PTCHD1AS1, PTCHD1AS2, PTCHD1AS3 Overlaps coding gene   Mutations in PTCHD1 locus are associated with autism spectrum disorder Mouse and human tissues, 10T1/2 cells ISH, overexpression (61
RASSF1A RASSF1A ANRASSF1 Overlaps coding gene Discordant ANRASSF1 forms an RNA/DNA hybrid, recruits PRC2 and increases H3K27me3 at RASSF1A promoter RASSF1A is a tumor suppressor HeLa, MDA-MB-231 and MCF-7 cells Overexpression, knockdown, RNA-IP, RNase-ChIP (62
RNGTT RNGTT HERV-Ec6 Antisense between exons 14 and 15 Discordant?  NAT expression is reduced in urothelial carcinoma Human tumors and urothelial cell line Expression profiling (16
SH3RF3 Sh3rf3 pancSh3rf3 Overlaps coding gene Concordant   Mouse and chimpanzee tissue samples Directional RNA-seq, strand-specific RT-PCR, knockdown (23
SPI1 PU.1 PU.1 Overlaps coding gene Discordant NAT inhibits PU.1 by forming RNA duplex and decreasing PU.1 mRNA association with eEF1A PU.1 expression is needed for suppression of leukemia HL-60 and RAW 264.7 cells Knockdown, expression profiling, RNA IP (63
STAR Star Star NAT Overlaps coding gene Discordant HCG stimulates Star NAT expression via cAMP STAR is important in steroidogenesis MA-10 Leydig cells, murine tissues Overexpression (64
SYNGAP1 SYNGAP1 SYNGAP1-AS Overlaps exons and promoter Discordant? NAT localized to nucleoplasm or chromatin SYNGAP1 AS is upregulated in autistic brain SH-SY5Y, normal and autistic brains Expression profiling (50
TFPI2 TFPI-2 TFPI-2as, LCT13 Overlaps coding gene Discordant Decreased TFPI-2 expression corresponds to increase in H3K9me3 and H4K20me3 TFPI-2 is a metastasis-suppressor gene Transgenic mouse ES, breast and colon cancer cell lines Overexpression, knockdown (65
TGFB TGFbeta1,3 TGFbeta2 Overlaps coding gene    Human and rodent tissues Northern, ISH with sense probe (66
TNFA TNF-α TNF-α asRNA Overlaps coding gene Discordant Reduces TNF-α mRNA stability?  Primary rat hepatocytes; human tumor and blood cells Knockdown (67
TNFSF9 4-1BBL Anti-4-1BBL/AK154177 Overlaps 5′ region and promoter Discordant?  TNFSF9 is involved in regulation of cytokine production Mouse macrophage cell line and primary macrophages Overexpression, expression profiling (54
TSPO TSPO Tspo-NAT Overlaps SINEB2 and exon 3 of Tspo Discordant cAMP increases Tspo-NAT expression Tspo is involved in the rate-limiting step in steroidogenesis MA-10 mouse tumor Leydig cells Overexpression, real-time PCR, western blot (20
TYMS thymidylate synthase rTSα Coding NAT, overlaps partner gene  Induces transformation of the adenosine to inosine nucleotide in sense pre-mRNA leading to downregulation  HeLa cells ISH, single cell real-time PCR, ribonuclease protection assay, knockdown, Northern (68
UCHL1 Uchl1 Antisense Uchl1 Overlaps coding gene  NAT is required for association of UCHL1 with polysomes for translation; NAT activity needs embedded SINEB2 Uchl1 is involved in brain function and neurodegenerative diseases Mouse cells Mutation analysis (19
VPS13B VPS13B VPS13B-AS Promoter  Localized to nucleoplasm or chromatin  SH-SY5Y, normal and autistic brains Expression profiling (50
VWA5B2 Vwa5b2 panc Vwa5b2 Overlaps coding gene Concordant   Mouse and chimpanzee tissue samples Directional RNA-seq, RT-PCR, knockdown (23
WDR83 WDR83 DHPS (protein coding) Overlaps coding gene, head to head Concordant, mutual WDR83 and DHPS form RNA duplex at overlapping 3′ UTRs which increases their stability WDR83 or DHPS promote cell proliferation in gastric cancer MGC803 cells (gastric cancer) Overexpression (25
Coding gene symbol Name used in reference NAT name NAT localization relative to coding gene Effect on coding gene expression Mechanism Therapeutic relevance Model Methods Ref. 
ADAM12 ADAM12 Inter genic10 Intergenic, overlaps 3′ end of ADAM12 Concordant NAT knockdown decreases H3K4me2 in the promoter region  Human fibroblast cells Deep sequencing, ChRIP (15
APOA1 APOA1 APOA1 NAT Overlaps coding gene cluster Discordant NAT recruits LSD1 and SUZ12, affects epigenetic marks at the three promoters APOA1 cluster is involved in cardiovascular disease Human and monkey cell lines and primary hepatocytes, monkeys ChIP, real-time PCR (41
APOA4 APOA4 APOA1 NAT Overlaps coding gene cluster Discordant NAT recruits LSD1 and SUZ12, affects epigenetic marks at the three promoters APOA1 cluster is involved in cardiovascular disease Human cell lines ChIP, real-time PCR (41
APOC3 APOC3 APOA1 NAT Overlaps coding gene cluster Discordant NAT recruits LSD1 and SUZ12, affects epigenetic marks at the three promoters APOA1 cluster is involved in cardiovascular disease Human cell lines ChIP, real-time PCR (41
BACE1 BACE1 BACE1-AS Overlaps coding gene Concordant NAT masks binding site for miR-485-5p BACE1-AS is upregulated in AD brains and is involved in regulation of Aβ 1–42 production APP transgenic mice, N2a and HEK293T C3 cells, human and mouse tissues, AD brains Knockdown, overexpression, mutation analysis, DiscoveRx (4244
BDNF BDNF BDNF-AS Overlaps coding gene Discordant NAT depletion reduced H3K27met3 and Ezh2 binding, but not H3K4met3 and H3K36met3 BDNF regulates neuronal outgrowth and differentiation Human and mouse cell lines, mice, cultured human neurons, glia, mouse neurospheres Knockdown in vivo and in vitro, ChIP, IHC (31
CDKN2B p15 (INK4B) ANRIL Overlaps coding gene Discordant? NAT is required for the recruitment of PRC2 and SUZ12 binding to p15(INK4B) INK4B is activated by carcinogens to stop cell propagation Human cell lines Knockdown (45
CDKN2B p15 p15AS Overlaps coding gene Discordant? NAT mediates CDKN2B repression in cis and in trans via heterochromatin formation, not DNA methylation; repression continued after NAT expression was turned off; dicer independent p15 is implicated in leukemia Mouse ESCs, leukemic leukocytes, human cell lines Expression profiling, overexpression (46
DHRS4, DHRS4L2, DHRS4L1 DHRS4, DHRS4L2, DHRS4L1 AS1DHRS4 Antisense in intron 1 of DHRS4 Discordant for all three genes NAT pairs with ongoing sense transcripts; mediates H3 deacetylation and H3K4 demethylation of DHRS4, interacts with G9a and EZH2 in DHRS4L2 and DHRS4L1 promoters DHRS4 is important for metabolism of organic compounds Normal human hepatic (HL7702) and hepatocellular carcinoma (HepG2) cells siRNA, RNA-ChIP (47
DLX1 Dlx1 Dlx1as Overlaps coding gene Discordant?   Embryonic mouse brain qPCR, ISH (48
DLX6 DLX6 DLX6-AS/Evf2 Head to head Discordant NAT recruits DLX and MECP2 to regulatory elements in intergenic region Evf2 mouse mutants had reduced synaptic inhibition Developing mouse brain, Evf2 loss-of-function mice Evf2 electroporation into brains, qChIP-PCR (49
EPH1B EPH1B EPH1B-AS Overlaps coding gene Discordant  EPHB1 is important in brain development and function Human cells Knockdown (31
FOXG1 FOXG1 FOXG1-AS Promoter Concordant?   SH-SY5Y, normal and autistic brains Expression profiling (50
GCCR GR Gas5 Overlaps coding gene  Gas5 bound to DNA-binding domain of GCCR through its hairpin #5 without altering the abundance of GCCR target genes Gas5 sensitized cells to apoptosis HeLa cells Yeast two-hybrid screen, GR-binding defective Gas5 mutant, ChiP, overexpression, mutation analysis (51
GDNF GDNF GDNF-AS Overlaps coding gene Discordant  EPHB1 is important in brain development and function Human cells Knockdown (31
HIF1A HIF1 alpha aHIF Complementary to the 3′ UTR Discordant?  NAT is overexpressed in non-papillary kidney cancer Renal carcinomas, normal lymphocyte cell line Ribonuclease protection, expression profiling (52
HRAS p21 p21 antisense Bidirectional transcription Discordant Ago-2 is required for NAT effect; loss of NAT correlates with loss of H3K27me3 at the p21 promoter  MCF-7 cells Nuclear run on analysis, ChIP (53
IL1A IL-1a Anti-IL-1a/AK042010 Overlaps coding gene Concordant?  NAT is involved in regulation of cytokine production Mouse macrophage cell line and primary macrophages Overexpression, ChIP, expression profiling (54
IL1B IL-1β Anti-IL-1β/ AK076405 Head to head, overlaps 5′ and promoter Discordant NAT inhibited IL1B at transcriptional level NAT is involved in regulation of cytokine production Mouse macrophage cell line and primary macrophages Overexpression, ChIP, expression profiling (54
IL4I1 IL-4i1 Anti-IL-4i1/ AK087754 Overlaps coding gene Concordant?  NAT is involved in regulation of cytokine production Mouse macrophage cell line and primary macrophages Overexpression, ChIP, expression profiling (54
KCNMB4 Kcnmb4 panc Kcnmb4 Bidirectional head to head Concordant   Mouse and chimpanzee tissue samples Directional RNA-seq, RT-PCR, knockdown (23
MSTN Myostatin Mstn promoter-associated RNA Promoter Concordant NAT knockdown increases H3K9me2, but not H3K27me3 at the Mstn promoter; histone deacetylase dependent Mstn negatively regulates muscle mass Differentiated mouse muscle cell lines and myoblasts with dystrophin mutation Knockdown, expression profiling (55
MYH Myosin heavy chain (MHC) bII NAT NAT starts in IIb-Neo intergenic region and overlaps IIb MHC Discordant  bII NAT is regulated during postnatal development and in response to hypothyroidism Developing rat muscle Expression profiling (56
MYH1 IIx MHC aII NAT NAT begins in the IIa–IIx intergenic region, overlaps IIa MHC Concordant?  NAT is involved in slow to fast MHC transformation Rat muscle after spinal cord isolation Expression profiling (57
MYH1 IIx MHC xII NAT Shares bidirectional promoter with IIb MHC, overlaps IIx Discordant?  Shift from IIb to IIx expression occurs after exercise Rat tissues Expression profiling (58
MYH2 IIa MHC aII NAT NAT begins in the IIa-IIx intergenic region, overlaps IIa Discordant?  NAT is involved in slow to fast MHC transformation Rat muscle after spinal cord isolation Expression profiling (57
MYH3 Neo MHC bII NAT Begins in IIb-Neo intergenic region and overlaps IIb Concordant?  NAT regulates transition between neo and IIb MHC Normal and thyroid-deficient rat neonates treated with PTU Expression profiling (56
MYH4 IIb MHC bII NAT Starts in IIb-Neo intergenic region and overlaps IIb Discordant?  NAT regulates transition between neo and IIb MHC Normal and PTU-treated rat neonates Expression profiling (56
NFKB1 p105 Anti-p105/AK090099 Overlaps coding gene Concordant?  NAT is involved in regulation of cytokine production Mouse macrophage cell line and LPS-activated primary macrophages Expression profiling (54
NFKB2 p100 Anti-p100/ AK029443 Head to head, overlaps the 5′ region and promoter Concordant?  NAT is involved in regulation of cytokine production Mouse macrophage cell line and LPS-activated primary macrophages Overexpression, expression profiling (54
NIPBL NIPBL NIPBL-AS Promoter  NAT localized to nucleoplasm or chromatin  SH-SY5Y, normal and autistic brains Expression profiling (50
NOS2A iNOS iNOS asRNA 3′UTR of rat and mouse iNOS Concordant NAT stabilizes iNOS mRNA Reducing iNOS mRNA levels is needed in inflammatory diseases and cancers Primary hepatocytes from LPS-treated rats; IL-1β-treated hepatocytes; human tumors Knockdown (59
PACSIN1 Pacsin1 panc Pacsin1 Bidirectional transcription Concordant   Mouse and chimpanzee tissue samples RNA-seq, knockdown (23
PINK1 PINK1 naPINK1 Overlaps coding gene Concordant?  PINK1 mutations are implicated in early-onset Parkinson's Neuronal cell lines Knockdown (60
PLA2G4A PLA2G4A HERV-Ec1 Between exons 7 and 8, in antisense orientation Discordant, mutual  NAT is downregulated in urothelial carcinoma Human tumors and urothelial cell line (UROtsa) Expression profiling, knockdown (16
PQBP1 PQBP1 PQBP1-AS Overlaps exons and promoter Discordant?   SH-SY5Y, normal and autistic brains Expression profiling (50
PTCHD1 PTCHD1 PTCHD1AS1, PTCHD1AS2, PTCHD1AS3 Overlaps coding gene   Mutations in PTCHD1 locus are associated with autism spectrum disorder Mouse and human tissues, 10T1/2 cells ISH, overexpression (61
RASSF1A RASSF1A ANRASSF1 Overlaps coding gene Discordant ANRASSF1 forms an RNA/DNA hybrid, recruits PRC2 and increases H3K27me3 at RASSF1A promoter RASSF1A is a tumor suppressor HeLa, MDA-MB-231 and MCF-7 cells Overexpression, knockdown, RNA-IP, RNase-ChIP (62
RNGTT RNGTT HERV-Ec6 Antisense between exons 14 and 15 Discordant?  NAT expression is reduced in urothelial carcinoma Human tumors and urothelial cell line Expression profiling (16
SH3RF3 Sh3rf3 pancSh3rf3 Overlaps coding gene Concordant   Mouse and chimpanzee tissue samples Directional RNA-seq, strand-specific RT-PCR, knockdown (23
SPI1 PU.1 PU.1 Overlaps coding gene Discordant NAT inhibits PU.1 by forming RNA duplex and decreasing PU.1 mRNA association with eEF1A PU.1 expression is needed for suppression of leukemia HL-60 and RAW 264.7 cells Knockdown, expression profiling, RNA IP (63
STAR Star Star NAT Overlaps coding gene Discordant HCG stimulates Star NAT expression via cAMP STAR is important in steroidogenesis MA-10 Leydig cells, murine tissues Overexpression (64
SYNGAP1 SYNGAP1 SYNGAP1-AS Overlaps exons and promoter Discordant? NAT localized to nucleoplasm or chromatin SYNGAP1 AS is upregulated in autistic brain SH-SY5Y, normal and autistic brains Expression profiling (50
TFPI2 TFPI-2 TFPI-2as, LCT13 Overlaps coding gene Discordant Decreased TFPI-2 expression corresponds to increase in H3K9me3 and H4K20me3 TFPI-2 is a metastasis-suppressor gene Transgenic mouse ES, breast and colon cancer cell lines Overexpression, knockdown (65
TGFB TGFbeta1,3 TGFbeta2 Overlaps coding gene    Human and rodent tissues Northern, ISH with sense probe (66
TNFA TNF-α TNF-α asRNA Overlaps coding gene Discordant Reduces TNF-α mRNA stability?  Primary rat hepatocytes; human tumor and blood cells Knockdown (67
TNFSF9 4-1BBL Anti-4-1BBL/AK154177 Overlaps 5′ region and promoter Discordant?  TNFSF9 is involved in regulation of cytokine production Mouse macrophage cell line and primary macrophages Overexpression, expression profiling (54
TSPO TSPO Tspo-NAT Overlaps SINEB2 and exon 3 of Tspo Discordant cAMP increases Tspo-NAT expression Tspo is involved in the rate-limiting step in steroidogenesis MA-10 mouse tumor Leydig cells Overexpression, real-time PCR, western blot (20
TYMS thymidylate synthase rTSα Coding NAT, overlaps partner gene  Induces transformation of the adenosine to inosine nucleotide in sense pre-mRNA leading to downregulation  HeLa cells ISH, single cell real-time PCR, ribonuclease protection assay, knockdown, Northern (68
UCHL1 Uchl1 Antisense Uchl1 Overlaps coding gene  NAT is required for association of UCHL1 with polysomes for translation; NAT activity needs embedded SINEB2 Uchl1 is involved in brain function and neurodegenerative diseases Mouse cells Mutation analysis (19
VPS13B VPS13B VPS13B-AS Promoter  Localized to nucleoplasm or chromatin  SH-SY5Y, normal and autistic brains Expression profiling (50
VWA5B2 Vwa5b2 panc Vwa5b2 Overlaps coding gene Concordant   Mouse and chimpanzee tissue samples Directional RNA-seq, RT-PCR, knockdown (23
WDR83 WDR83 DHPS (protein coding) Overlaps coding gene, head to head Concordant, mutual WDR83 and DHPS form RNA duplex at overlapping 3′ UTRs which increases their stability WDR83 or DHPS promote cell proliferation in gastric cancer MGC803 cells (gastric cancer) Overexpression (25

Generation of endogenous siRNAs and miRNA/modulation of mRNA stability

The first proposed mechanism of NAT-mediated gene expression regulation was based on the presence of overlapping exons between NATs and their sense gene partners as well as known information about how siRNA/miRNA acts upon messenger RNA. This evidence was used to formulate the theory that sense/antisense RNA duplex formation during or after transcription leads to either sense transcript degradation or stabilization. This mechanism overlaps with another suggested function of ncRNAs, namely serving as precursors for endogenous siRNAs and miRNA production. Although multiple examples of gene expression regulation through sense–antisense RNA interaction are known (Table 1), it is likely that these mechanisms are not very widespread, because only 1% of the genome is transcribed from both plus and minus strands (23).

The biological importance of the sense–antisense RNA interaction is supported by recent findings showing that a subset of lncRNA is enriched in the cytosol and in ribosomal fractions rather than in the nucleus (69). In mouse CD4+ T cells multiple endogenous siRNA and miRNA transcripts were identified. These transcripts interacted with argonaute (AGO) proteins that mediated RNA interference and posttranscriptional gene silencing (32). Short RNA-seq and cross linking, ligation and sequencing of hybrids of human embryonic kidney cell (HEK293) RNA yielded antisense transcripts from 378 genes with a characteristic endo-siRNA footprint (co-occurrence of RNAPII and AGO1); (33).

lncRNA in stabilization of long-range chromosomal interactions

Advanced methods, including chromatin conformation capture and its modifications, 4C, 5C and Hi-C (13), have revealed long-range chromosomal interactions in B- and T-cell receptor loci (reviewed in 70). Multiple chromatin loops in these loci may form rosette-like structures that bring distant chromosomal regions into the same transcription factory. These structures may be formed with participation of CTCF and cohesin proteins and lncRNAs.

THERAPEUTIC APPLICATIONS OF NATS

The high target specificity of NATs that normally regulate one gene or a small group of related genes makes them a welcome addition to the list of targets available for therapeutic intervention. A growing number of NATs in disease-relevant loci is being characterized (Tables 1 and 2). Although functional NATs were described as early as mid-1990, the therapeutic application for them was not proposed until mid-2000s (81). Whereas some authors suggest using NATs and other lncRNAs for gene downregulation (55), a more unique therapeutic aspect of NATs is their ability to increase the expression of specific genes (12,8285). This approach is currently being brought into practice by at least two biotechnology companies utilizing related NAT-targeting technologies: (i) oligonucleotides interfering with NAT function through steric hindrance or RNAse H-mediated degradation (OPKO CURNA, Miramar, FL, USA; founded 2008) and (ii) oligonucleotides targeting NAT interaction with PRC2 (RaNA, Cambridge, MA, USA; founded 2011). Additionally, manipulation of regulatory pseudogene transcripts through the use of synthetic antisense oligonucleotides, siRNAs, aptamers or gene therapy has been proposed as a novel pharmacological strategy (21). An algorithm to design short ncRNAs for the epigenetic transcriptional silencing or activation of specific genes has been published (86).

Table 2.

NATs involved in rare genetic disorders

Coding gene symbol Name used in reference NAT name NAT localization relative to coding gene Effect on coding gene expression Mechanism Therapeutic relevance Model Methods Ref. 
ARHGEF26 ARHGEF26 AK087060 Starts 225 bps downstream of the coding gene Concordant?  Mecp2 is mutated in Rett syndrome Brain of Rett syndrome mice Overexpression, microarray, ChIP, bisulfite genomic sequencing (71
ATXN7 Ataxin-7 SCAANT1 Overlaps coding gene Discordant NAT induces repression in cis-, accompanied by increase in H3K27me3 and decrease in H3 acetylation at ATXN7 promoter; overexpression of NAT did not affect ATXN7 In SCA7, SCAANT1 is decreased and ATXN7 is increased Mice with ataxin-7 mini-genes, human retinoblastoma cell lines, primary cerebellar astrocytes ChIP, deletion analysis, overexpression (72
ATXN8 ATXN8 ATXN8OS, protein coding Overlaps coding gene   ATXN8 is mutated in SCA8 Human cell lines Expression profiling (73
FMR1 FMR1 FMR4 or FMR1-AS1 Bidirectional transcription None  FMR4 and FMR1 are silenced in fragile X patients and upregulated in premutation carriers Human and monkey tissues, HEK293T, HeLa cells Knockdown, overexpression, expression profiling (74
FMR1 FMR1 FMR6 Overlaps the 3′ of FMR1, antisense   FMR6 is silenced in full Fragile X Syndrome mutation and permutation carriers Human tissues, leukocytes Expression profiling, deep RACE, next generation sequencing (75
GABRR2 Gabrr2 AK081227 (same direct as coding) Intron of Gabrr2 Discordant?  Involved in Rett syndrome Brain of Rett syndrome mice Overexpression, microarray, ChIP, bisulfite genomic sequencing (71
HTT HTT HTTAS Overlaps coding gene Discordant NAT effect is Dicer-dependent, repeat expansion reduces expression HTTAS is reduced in human HD Human cells Overexpression, siRNA (76
KLHL1 KLHL1 SCA8, KLHL1AS Overlaps coding gene   NAT contributes to neurotoxicity in SCA9 Human and mouse tissues Expression profiling (77
MKRN3 ZNF127 ZNF127AS, MKRN3-AS1 Overlaps coding gene, transcribed only from paternal allele   Prader–Willi syndrome is caused by deletion on the paternal chromosome including MKRN3/ZNF127 Human and mouse tissues Expression profiling (78
SCA8 SCA8  Overlaps coding gene   NAT contributes to neurotoxicity in SCA8 HEK293 and SH-SY5Y cells Expression profiling (79
UBE3A Ube3a Ube3a-as Overlaps coding gene Discordant  Involved in Angelman syndrome Transgenic mice Mutational mapping, expression profiling (80
Coding gene symbol Name used in reference NAT name NAT localization relative to coding gene Effect on coding gene expression Mechanism Therapeutic relevance Model Methods Ref. 
ARHGEF26 ARHGEF26 AK087060 Starts 225 bps downstream of the coding gene Concordant?  Mecp2 is mutated in Rett syndrome Brain of Rett syndrome mice Overexpression, microarray, ChIP, bisulfite genomic sequencing (71
ATXN7 Ataxin-7 SCAANT1 Overlaps coding gene Discordant NAT induces repression in cis-, accompanied by increase in H3K27me3 and decrease in H3 acetylation at ATXN7 promoter; overexpression of NAT did not affect ATXN7 In SCA7, SCAANT1 is decreased and ATXN7 is increased Mice with ataxin-7 mini-genes, human retinoblastoma cell lines, primary cerebellar astrocytes ChIP, deletion analysis, overexpression (72
ATXN8 ATXN8 ATXN8OS, protein coding Overlaps coding gene   ATXN8 is mutated in SCA8 Human cell lines Expression profiling (73
FMR1 FMR1 FMR4 or FMR1-AS1 Bidirectional transcription None  FMR4 and FMR1 are silenced in fragile X patients and upregulated in premutation carriers Human and monkey tissues, HEK293T, HeLa cells Knockdown, overexpression, expression profiling (74
FMR1 FMR1 FMR6 Overlaps the 3′ of FMR1, antisense   FMR6 is silenced in full Fragile X Syndrome mutation and permutation carriers Human tissues, leukocytes Expression profiling, deep RACE, next generation sequencing (75
GABRR2 Gabrr2 AK081227 (same direct as coding) Intron of Gabrr2 Discordant?  Involved in Rett syndrome Brain of Rett syndrome mice Overexpression, microarray, ChIP, bisulfite genomic sequencing (71
HTT HTT HTTAS Overlaps coding gene Discordant NAT effect is Dicer-dependent, repeat expansion reduces expression HTTAS is reduced in human HD Human cells Overexpression, siRNA (76
KLHL1 KLHL1 SCA8, KLHL1AS Overlaps coding gene   NAT contributes to neurotoxicity in SCA9 Human and mouse tissues Expression profiling (77
MKRN3 ZNF127 ZNF127AS, MKRN3-AS1 Overlaps coding gene, transcribed only from paternal allele   Prader–Willi syndrome is caused by deletion on the paternal chromosome including MKRN3/ZNF127 Human and mouse tissues Expression profiling (78
SCA8 SCA8  Overlaps coding gene   NAT contributes to neurotoxicity in SCA8 HEK293 and SH-SY5Y cells Expression profiling (79
UBE3A Ube3a Ube3a-as Overlaps coding gene Discordant  Involved in Angelman syndrome Transgenic mice Mutational mapping, expression profiling (80

The two main areas for which ncRNA-based therapies are now being developed are cancers and rare genetic disorders. Cancer applications are mostly based on lincRNAs (reviewed in 8789). Examples of ncRNAs likely associated with rare genetic disorders are given in Table 2 and have been recently reviewed (90).

CONCLUSIONS

After a long struggle, studies of lncRNAs including NATs are now expanding at a very high rate, leading to the understanding of the major role of RNA in the functioning of the genome as well as the discovery of novel targets for therapeutic intervention.

Conflict of Interest statement. None declared.

FUNDING

NIH funded, grant numbers 1R01MH084880, R01MH083733 and R01NS063974.

REFERENCES

1
Amaral
P.P.
Dinger
M.E.
Mercer
T.R.
Mattick
J.S.
The eukaryotic genome as an RNA machine
Science
 
2008
319
1787
1789
2
Katayama
S.
Tomaru
Y.
Kasukawa
T.
Waki
K.
Nakanishi
M.
Nakamura
M.
Nishida
H.
Yap
C.C.
Suzuki
M.
Kawai
J.
et al.  
Antisense transcription in the mammalian transcriptome
Science
 
2005
309
1564
1566
3
Derrien
T.
Johnson
R.
Bussotti
G.
Tanzer
A.
Djebali
S.
Tilgner
H.
Guernec
G.
Martin
D.
Merkel
A.
Knowles
D.G.
et al.  
The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression
Genome Res.
 
2012
22
1775
1789
4
Carninci
P.
Kasukawa
T.
Katayama
S.
Gough
J.
Frith
M.C.
Maeda
N.
Oyama
R.
Ravasi
T.
Lenhard
B.
Wells
C.
et al.  
The transcriptional landscape of the mammalian genome
Science
 
2005
309
1559
1563
5
Djebali
S.
Davis
C.A.
Merkel
A.
Dobin
A.
Lassmann
T.
Mortazavi
A.
Tanzer
A.
Lagarde
J.
Lin
W.
Schlesinger
F.
et al.  
Landscape of transcription in human cells
Nature
 
2012
489
101
108
6
Bernstein
B.E.
Birney
E.
Dunham
I.
Green
E.D.
Gunter
C.
Snyder
M.
ENCODE Project Consortium
An integrated encyclopedia of DNA elements in the human genome
Nature
 
2012
489
57
74
7
Rinn
J.L.
Chang
H.Y.
Genome regulation by long noncoding RNAs
Annu. Rev. Biochem.
 
2012
81
145
166
8
Candeias
M.M.
Malbert-Colas
L.
Powell
D.J.
Daskalogianni
C.
Maslon
M.M.
Naski
N.
Bourougaa
K.
Calvo
F.
Fåhraeus
R.
P53 mRNA controls p53 activity by managing Mdm2 functions
Nat. Cell Biol.
 
2008
10
1098
1105
9
Leygue
E.
Steroid receptor RNA activator (SRA1): unusual bifaceted gene products with suspected relevance to breast cancer
Nucl. Recept. Signal.
 
2007
5
e006
10
Khalil
A.M.
Wahlestedt
C.
Epigenetic mechanisms of gene regulation during mammalian spermatogenesis
Epigenetics
 
2008
3
21
28
11
Lee
J.T.
Gracefully ageing at 50, X-chromosome inactivation becomes a paradigm for RNA and chromatin control
Nat. Rev. Mol. Cell. Biol.
 
2011
12
815
826
12
Wahlestedt
C.
Targeting long non-coding RNA to therapeutically upregulate gene expression
Nat. Rev. Drug Discov.
 
2013
6
433
446
13
Johnsson
P.
Lipovich
L.
Grandér
D.
Morris
K.V.
Evolutionary conservation of long non-coding RNAs; sequence, structure, function
Biochim. Biophys. Acta
 
2014
1840
1063
1071
14
Khaitovich
P.
Kelso
J.
Franz
H.
Visagie
J.
Giger
T.
Joerchel
S.
Petzold
E.
Green
R.E.
Lachmann
M.
Pääbo
S.
Functionality of intergenic transcription: an evolutionary comparison
PLoS Genet.
 
2006
2
e171
15
Mondal
T.
Rasmussen
M.
Pandey
G.K.
Isaksson
A.
Kanduri
C.
Characterization of the RNA content of chromatin
Genome Res.
 
2010
20
899
907
16
Gosenca
D.
Gabriel
U.
Steidler
A.
Mayer
J.
Diem
O.
Erben
P.
Fabarius
A.
Leib-Mösch
C.
Hofmann
W.K.
Seifarth
W.
HERV-E-mediated modulation of PLA2G4A transcription in urothelial carcinoma
PLoS ONE
 
2012
7
e49341
17
Conley
A.B.
Miller
W.J.
Jordan
I.K.
Human cis natural antisense transcripts initiated by transposable elements
Trends Genet.
 
2008
24
53
56
18
Dai
Y.
Li
S.
Dong
X.
Sun
H.
Li
C.
Liu
Z.
Ying
B.
Ding
G.
Li
Y.
The de novo sequence origin of two long non-coding genes from an inter-genic region
BMC Genomics
 
2013
8
S6
19
Carrieri
C.
Cimatti
L.
Biagioli
M.
Beugnet
A.
Zucchelli
S.
Fedele
S.
Pesce
E.
Ferrer
I.
Collavin
L.
Santoro
C
et al.  
Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat
Nature
 
2012
491
454
457
20
Fan
J.
Papadopoulos
V.
Transcriptional regulation of translocator protein (Tspo) via a SINE B2-mediated natural antisense transcript in MA-10 Leydig cells
Biol. Reprod.
 
2012
86
1
15
21
Roberts
T.C.
Morris
K.V.
Not so pseudo anymore: pseudogenes as therapeutic targets
Pharmacogenomics
 
2013
4
2023
2034
22
Batagov
A.O.
Yarmishyn
A.A.
Jenjaroenpun
P.
Tan
J.Z.
Nishida
Y.
Kurochkin
I.V.
Role of genomic architecture in the expression dynamics of long noncoding RNAs during differentiation of human neuroblastoma cells
BMC Syst. Biol.
 
2013
7
S11
23
Uesaka
M.
Nishimura
O.
Go
Y.
Nakashima
K.
Agata
K.
Imamura
T.
Bidirectional promoters are the major source of gene activation-associated non-coding RNAs in mammals
BMC Genomics
 
2014
15
35
24
Lepoivre
C.
Belhocine
M.
Bergon
A.
Griffon
A.
Yammine
M.
Vanhille
L.
Zacarias-Cabeza
J.
Garibal
M.A.
Koch
F.
Maqbool
M.A.
et al.  
Divergent transcription is associated with promoters of transcriptional regulators
BMC Genomics
 
2013
14
914
25
Su
W.Y.
Li
J.T.
Cui
Y.
Hong
J.
Du
W.
Wang
Y.C.
Lin
Y.W.
Xiong
H.
Wang
J.L.
Kong
X.
et al.  
Bidirectional regulation between WDR83 and its natural antisense transcript DHPS in gastric cancer
Cell Res.
 
2012
22
1374
1389
26
Sigova
A.A.
Mullen
A.C.
Molinie
B.
Gupta
S.
Orlando
D.A.
Guenther
M.G.
Almada
A.E.
Lin
C.
Sharp
P.A.
Giallourakis
C.C.
et al.  
Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells
Proc. Natl. Acad. Sci. USA
 
2013
110
2876
2881
27
Tan-Wong
S.M.
Zaugg
J.B.
Camblong
J.
Xu
Z.
Zhang
D.W.
Mischo
H.E.
Ansari
A.Z.
Luscombe
N.M.
Steinmetz
L.M.
Proudfoot
N.J.
Gene loops enhance transcriptional directionality
Science
 
2012
338
671
675
28
Pulakanti
K.
Pinello
L.
Stelloh
C.
Blinka
S.
Allred
J.
Milanovich
S.
Kiblawi
S.
Peterson
J.
Wang
A.
Yuan
G.C.
et al.  
Enhancer transcribed RNAs arise from hypomethylated, Tet-occupied genomic regions
Epigenetics
 
2013
8
1303
1320
29
Huang
J.
Zhou
N.
Watabe
K.
Lu
Z.
Wu
F.
Xu
M.
Mo
Y.Y.
Long non-coding RNA UCA1 promotes breast tumor growth by suppression of p27 (Kip1)
Cell Death Dis.
 
2014
5
e1008
30
Wang
K.
Liu
F.
Zhou
L.Y.
Long
B.
Yuan
S.M.
Wang
Y.
Liu
C.Y.
Sun
T.
Zhang
X.J.
Li
P.F.
The long noncoding RNA, CHRF regulates cardiac hypertrophy by targeting miR-489
Circ. Res.
 
2014
114
1377
1388
31
Modarresi
F.
Faghihi
M.A.
Lopez-Toledano
M.A.
Fatemi
R.P.
Magistri
M.
Brothers
S.P.
van der Brug
M.P.
Wahlestedt
C.
Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation
Nat. Biotechnol.
 
2012
30
453
459
32
Polikepahad
S.
Corry
D.B.
Profiling of T helper cell-derived small RNAs reveals unique antisense transcripts and differential association of miRNAs with argonaute proteins 1 and 2
Nucleic Acids Res.
 
2013
41
1164
1177
33
Werner
A.
Cockell
S.
Falconer
J.
Carlile
M.
Alnumeir
S.
Robinson
J.
Contribution of natural antisense transcription to an endogenous siRNA signature in human cells
BMC Genomics
 
2014
15
19
34
Froberg
J.E.
Yang
L.
Lee
J.T.
Guided by RNAs: X-inactivation as a model for lncRNA function
J. Mol. Biol.
 
2013
425
3698
3706
35
Margueron
R.
Reinberg
D.
The polycomb complex PRC2 and its mark in life
Nature
 
2011
469
343
349
36
Davidovich
C.
Zheng
L.
Goodrich
K.J.
Cech
T.R.
Promiscuous RNA binding by polycomb repressive complex 2
Nat. Struct. Mol. Biol.
 
2013
20
1250
1257
37
Kaneko
S.
Bonasio
R.
Saldaña-Meyer
R.
Yoshida
T.
Son
J.
Nishino
K.
Umezawa
A.
Reinberg
D.
Interactions between JARID2 and noncoding RNAs regulate PRC2 recruitment to chromatin
Mol. Cell
 
2014
53
290
300
38
Kaneko
S.
Son
J.
Shen
S.S.
Reinberg
D.
Bonasio
R.
PRC2 binds active promoters and contacts nascent RNAs in embryonic stem cells
Nat. Struct. Mol. Biol.
 
2013
20
1258
1264
39
van Heeringen
S.J.
Akkers
R.C.
van Kruijsbergen
I.
Arif
M.A.
Hanssen
L.L.
Sharifi
N.
Veenstra
G.J.
Principles of nucleation of H3K27 methylation during embryonic development
Genome Res.
 
2014
24
401
410
40
Cerase
A.
Smeets
D.
Tang
Y.A.
Gdula
M.
Kraus
F.
Spivakov
M.
Moindrot
B.
Leleu
M.
Tattermusch
A.
Demmerle
J.
et al.  
Spatial separation of Xist RNA and polycomb proteins revealed by superresolution microscopy
Proc. Natl. Acad. Sci. USA
 
2014
111
2235
2540
41
Halley
P.
Kadakkuzha
B.M.
Faghihi
M.A.
Magistri
M.
Zeier
Z.
Khorkova
O.
Coito
C.
Hsiao
J.
Lawrence
M.
Wahlestedt
C.
Regulation of the apolipoprotein gene cluster by a long noncoding RNA
Cell Rep.
 
2014
6
222
230
42
Modarresi
F.
Faghihi
M.A.
Patel
N.S.
Sahagan
B.G.
Wahlestedt
C.
Lopez-Toledano
M.A.
Knockdown of BACE1-AS nonprotein-coding transcript modulates beta-amyloid-related hippocampal neurogenesis
Int. J. Alzheimers Dis.
 
2011
2011
929042
43
Faghihi
M.A.
Modarresi
F.
Khalil
A.M.
Wood
D.E.
Sahagan
B.G.
Morgan
T.E.
Finch
C.E.
St Laurent
G.
III
Kenny
P.J.
Wahlestedt
C.
Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase
Nat. Med.
 
2008
14
723
730
44
Faghihi
M.A.
Zhang
M.
Huang
J.
Modarresi
F.
Van der Brug
M.P.
Nalls
M.A.
Cookson
M.R.
St-Laurent
G.
III
Wahlestedt
C.
Evidence for natural antisense transcript-mediated inhibition of microRNA function
Genome Biol.
 
2010
11
R56
45
Kotake
Y.
Nakagawa
T.
Kitagawa
K.
Suzuki
S.
Liu
N.
Kitagawa
M.
Xiong
Y.
Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene
Oncogene
 
2011
30
1956
1962
46
Yu
W.
Gius
D.
Onyango
P.
Muldoon-Jacobs
K.
Karp
J.
Feinberg
A.P.
Cui
H.
Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA
Nature
 
2011
451
202
206
47
Li
Q.
Su
Z.
Xu
X.
Liu
G.
Song
X.
Wang
R.
Sui
X.
Liu
T.
Chang
X.
Huang
D.
AS1DHRS4, a head-to-head natural antisense transcript, silences the DHRS4 gene cluster in cis and trans
Proc. Natl. Acad. Sci. USA
 
2012
109
14110
14115
48
Wu
Z.
Zhao
A.N.
Zhu
L.Y.
Yin
B.
Zhang
J.
Role of Dlx1 natural antisense transcript in mice brain development
Zhongguo Yi Xue Ke Xue Yuan Xue Bao
 
2013
35
607
610
49
Bond
A.M.
Vangompel
M.J.
Sametsky
E.A.
Clark
M.F.
Savage
J.C.
Disterhoft
J.F.
Kohtz
J.D.
Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry
Nat. Neurosci.
 
2009
12
1020
1027
50
Velmeshev
D.
Magistri
M.
Faghihi
M.A.
Expression of non-protein-coding antisense RNAs in genomic regions related to autism spectrum disorders
Mol. Autism
 
2013
4
32
51
Kino
T.
Hurt
D.E.
Ichijo
T.
Nader
N.
Chrousos
G.P.
Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor
Sci. Signal.
 
2010
3
ra8
52
Thrash-Bingham
C.A.
Tartof
K.D.
aHIF: a natural antisense transcript overexpressed in human renal cancer and during hypoxia
J. Natl. Cancer Inst.
 
1999
91
143
151
53
Morris
K.V.
Santoso
S.
Turner
A.M.
Pastori
C.
Hawkins
P.G.
Bidirectional transcription directs both transcriptional gene activation and suppression in human cells
PLoS Genet.
 
2008
4
e1000258
54
Lu
J.
Wu
X.
Hong
M.
Tobias
P.
Han
J.
A potential suppressive effect of natural antisense IL-1β RNA on lipopolysaccharide-induced IL-1β expression
J. Immunol.
 
2013
190
6570
6578
55
Roberts
T.C.
Andaloussi
S.E.
Morris
K.V.
McClorey
G.
Wood
M.J.
Small RNA-mediated epigenetic myostatin silencing
Mol. Ther. Nucleic Acids
 
2012
1
e23
56
Pandorf
C.E.
Jiang
W.
Qin
A.X.
Bodell
P.W.
Baldwin
K.M.
Haddad
F.
Regulation of an antisense RNA with the transition of neonatal to IIb myosin heavy chain during postnatal development and hypothyroidism in rat skeletal muscle
Am. J. Physiol. Regul. Integr. Comp. Physiol.
 
2012
302
R854
R867
57
Pandorf
C.E.
Haddad
F.
Roy
R.R.
Qin
A.X.
Edgerton
V.R.
Baldwin
K.M.
Dynamics of myosin heavy chain gene regulation in slow skeletal muscle: role of natural antisense RNA
J. Biol. Chem.
 
2006
281
38330
38342
58
Rinaldi
C.
Haddad
F.
Bodell
P.W.
Qin
A.X.
Jiang
W.
Baldwin
K.M.
Intergenic bidirectional promoter and cooperative regulation of the IIx and IIb MHC genes in fast skeletal muscle
Am. J. Physiol. Regul. Integr. Comp. Physiol.
 
2008
295
R208
R218
59
Yoshigai
E.
Hara
T.
Araki
Y.
Tanaka
Y.
Oishi
M.
Tokuhara
K.
Kaibori
M.
Okumura
T.
Kwon
A.H.
Nishizawa
M.
Natural antisense transcript-targeted regulation of inducible nitric oxide synthase mRNA levels
Nitric Oxide
 
2013
30
9
16
60
Scheele
C.
Petrovic
N.
Faghihi
M.A.
Lassmann
T.
Fredriksson
K.
Rooyackers
O.
Wahlestedt
C.
Good
L.
Timmons
J.A.
The human PINK1 locus is regulated in vivo by a non-coding natural antisense RNA during modulation of mitochondrial function
BMC Genomics
 
2007
8
74
61
Noor
A.
Whibley
A.
Marshall
C.R.
Gianakopoulos
P.J.
Piton
A.
Carson
A.R.
Orlic-Milacic
M.
Lionel
A.C.
Sato
D.
Pinto
D.
et al.  
Disruption at the PTCHD1 Locus on Xp22.11 in Autism spectrum disorder and intellectual disability
Sci. Transl. Med.
 
2010
2
49ra68
62
Beckedorff
F.C.
Ayupe
A.C.
Crocci-Souza
R.
Amaral
M.S.
Nakaya
H.I.
Soltys
D.T.
Menck
C.F.
Reis
E.M.
Verjovski-Almeida
S.
The intronic long noncoding RNA ANRASSF1 recruits PRC2 to the RASSF1A promoter, reducing the expression of RASSF1A and increasing cell proliferation
PLoS Genet.
 
2013
9
e1003705
63
Ebralidze
A.K.
Guibal
F.C.
Steidl
U.
Zhang
P.
Lee
S.
Bartholdy
B.
Jorda
M.A.
Petkova
V.
Rosenbauer
F.
Huang
G.
et al.  
PU.1 expression is modulated by the balance of functional sense and antisense RNAs regulated by a shared cis-regulatory element
Genes Dev.
 
2008
22
2085
2092
64
Castillo
A.F.
Fan
J.
Papadopoulos
V.
Podestá
E.J.
Hormone-dependent expression of a steroidogenic acute regulatory protein natural antisense transcript in MA-10 mouse tumor Leydig cells
PLoS ONE
 
2011
6
e22822
65
Cruickshanks
H.A.
Vafadar-Isfahani
N.
Dunican
D.S.
Lee
A.
Sproul
D.
Lund
J.N.
Meehan
R.R.
Tufarelli
C.
Expression of a large LINE-1-driven antisense RNA is linked to epigenetic silencing of the metastasis suppressor gene TFPI-2 in cancer
Nucleic Acids Res.
 
2013
41
6857
6869
66
Coker
R.K.
Laurent
G.J.
Dabbagh
K.
Dawson
J.
McAnulty
R.J.
A novel transforming growth factor beta2 antisense transcript in mammalian lung
Biochem. J.
 
1998
332
297
301
67
Yoshigai
E.
Hara
T.
Inaba
H.
Hashimoto
I.
Tanaka
Y.
Kaibori
M.
Kimura
T.
Okumura
T.
Kwon
A.H.
Nishizawa
M.
Interleukin-1β induces tumor necrosis factor-α secretion from rat hepatocytes
Hepatol. Res.
 
2013
44
571
583
68
Faghihi
M.A.
Wahlestedt
C.
RNA interference is not involved in natural antisense mediated regulation of gene expression in mammals
Genome Biol.
 
2006
7
R38
69
van Heesch
S.
van Iterson
M.
Jacobi
J.
Boymans
S.
Essers
P.B.
de Bruijn
E.
Hao
W.
Macinnes
A.W.
Cuppen
E.
Simonis
M.
Extensive localization of long noncoding RNAs to the cytosol and mono- and polyribosomal complexes
Genome Biol.
 
2014
15
R6
70
Choi
N.M.
Feeney
A.J.
CTCF and ncRNA regulate the three-dimensional structure of antigen receptor loci to facilitate V(D)J recombination
Front. Immunol.
 
2014
5
49
71
Petazzi
P.
Sandoval
J.
Szczesna
K.
Jorge
O.C.
Roa
L.
Sayols
S.
Gomez
A.
Huertas
D.
Esteller
M.
Dysregulation of the long non-coding RNA transcriptome in a Rett syndrome mouse model
RNA Biol.
 
2013
10
1197
1203
72
Sopher
B.L.
Ladd
P.D.
Pineda
V.V.
Libby
R.T.
Sunkin
S.M.
Hurley
J.B.
Thienes
C.P.
Gaasterland
T.
Filippova
G.N.
La Spada
A.R.
CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA
Neuron
 
2011
70
1071
1084
73
Chen
I.C.
Lin
H.Y.
Hsiao
Y.C.
Chen
C.M.
Wu
Y.R.
Shiau
H.C.
Shen
Y.F.
Huang
K.S.
Su
M.T.
Hsieh-Li
H.M.
et al.  
Internal ribosome entry segment activity of ATXN8 opposite strand RNA
PLoS ONE
 
2013
8
e73885
74
Khalil
A.M.
Faghihi
M.A.
Modarresi
F.
Brothers
S.P.
Wahlestedt
C.
A novel RNA transcript with antiapoptotic function is silenced in fragile X syndrome
PLoS ONE
 
2008
3
e1486
75
Pastori
C.
Peschansky
V.J.
Barbouth
D.
Mehta
A.
Silva
J.P.
Wahlestedt
C.
Comprehensive analysis of the transcriptional landscape of the human FMR1 gene reveals two new long noncoding RNAs differentially expressed in Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome
Hum. Genet.
 
2014
133
59
67
76
Chung
D.W.
Rudnicki
D.D.
Yu
L.
Margolis
R.L.
A natural antisense transcript at the Huntington's disease repeat locus regulates HTT expression
Hum. Mol. Genet.
 
2011
20
3467
3477
77
Nemes
J.P.
Benzow
K.A.
Moseley
M.L.
Ranum
L.P.
Koob
M.D.
The SCA8 transcript is an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1)
Hum. Mol. Genet.
 
2000
9
1543
1551
78
Jong
M.T.
Gray
T.A.
Ji
Y.
Glenn
C.C.
Saitoh
S.
Driscoll
D.J.
Nicholls
R.D.
A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader-Willi syndrome critical region
Hum. Mol. Genet.
 
1999
8
783
793
79
Koob
M.D.
Moseley
M.L.
Schut
L.J.
Benzow
K.A.
Bird
T.D.
Day
J.W.
Ranum
L.P.
An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8)
Nat. Genet.
 
1999
21
379
384
80
Johnstone
K.A.
DuBose
A.J.
Futtner
C.R.
Elmore
M.D.
Brannan
C.I.
Resnick
J.L.
A human imprinting centre demonstrates conserved acquisition but diverged maintenance of imprinting in a mouse model for Angelman syndrome imprinting defects
Hum. Mol. Genet.
 
2006
15
393
404
81
Wahlestedt
C.
Natural antisense and noncoding RNA transcripts as potential drug targets
Drug Disc. Today
 
2006
11
503
508
82
Schwartz
J.C.
Younger
S.T.
Nguyen
N.B.
Hardy
D.B.
Monia
B.P.
Corey
D.R.
Janowski
B.A.
Antisense transcripts are targets for activating small RNAs
Nat. Struct. Mol. Biol.
 
2008
15
842
848
83
Morris
K.V.
Long antisense non-coding RNAs function to direct epigenetic complexes that regulate transcription in human cells
Epigenetics
 
2009
4
296
301
84
Halley
P.
Khorkova
O.
Wahlestedt
C.
Natural antisense transcripts as therapeutic targets
Drug Disc. Today: Ther. Strateg.
 
2013
10
1016
85
Zhao
J.
Ohsumi
T.K.
Kung
J.T.
Ogawa
Y.
Grau
D.J.
Sarma
K.
Song
J.J.
Kingston
R.E.
Borowsky
M.
Lee
J.T.
Genome-wide identification of polycomb-associated RNAs by RIP-seq
Mol. Cell
 
2010
40
939
953
86
Ackley
A.
Lenox
A.
Stapleton
K.
Knowling
S.
Lu
T.
Sabir
K.S.
Vogt
P.K.
Morris
K.V.
An algorithm for generating small RNAs capable of epigenetically modulating transcriptional gene silencing and activation in human cells
Mol. Ther. Nucleic Acids
 
2013
2
e104
87
Li
C.H.
Chen
Y.
Targeting long non-coding RNAs in cancers: progress and prospects
Int. J. Biochem. Cell Biol.
 
2013
45
1895
1910
88
Clarke
J.
Penas
C.
Pastori
C.
Komotar
R.J.
Bregy
A.
Shah
A.H.
Wahlestedt
C.
Ayad
N.G.
Epigenetic pathways and glioblastoma treatment
Epigenetics
 
2013
8
785
795
89
Tufarelli
C.
Cruickshanks
H.A.
Meehan
R.R.
LINE-1 activation and epigenetic silencing of suppressor genes in cancer: causally related events?
Mob. Genet. Elements
 
2013
3
e26832
90
van Devondervoort
I.I.
Gordebeke
P.M.
Khoshab
N.
Tiesinga
P.H.
Buitelaar
J.K.
Kozicz
T.
Aschrafi
A.
Glennon
J.C.
Long non-coding RNAs in neurodevelopmental disorders
Front. Mol. Neurosci.
 
2013
6
53