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MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA-DNA triplex structures.

Mondal T, Subhash S, Vaid R, Enroth S, Uday S, Reinius B, Mitra S, Mohammed A, James AR, Hoberg E, Moustakas A, Gyllensten U, Jones SJ, Gustafsson CM, Sims AH, Westerlund F, Gorab E, Kanduri C - Nat Commun (2015)

Bottom Line: MEG3 binding sites have GA-rich sequences, which guide MEG3 to the chromatin through RNA-DNA triplex formation.We have found that RNA-DNA triplex structures are widespread and are present over the MEG3 binding sites associated with the TGF-β pathway genes.Our findings suggest that RNA-DNA triplex formation could be a general characteristic of target gene recognition by the chromatin-interacting lncRNAs.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, Sweden.

ABSTRACT
Long noncoding RNAs (lncRNAs) regulate gene expression by association with chromatin, but how they target chromatin remains poorly understood. We have used chromatin RNA immunoprecipitation-coupled high-throughput sequencing to identify 276 lncRNAs enriched in repressive chromatin from breast cancer cells. Using one of the chromatin-interacting lncRNAs, MEG3, we explore the mechanisms by which lncRNAs target chromatin. Here we show that MEG3 and EZH2 share common target genes, including the TGF-β pathway genes. Genome-wide mapping of MEG3 binding sites reveals that MEG3 modulates the activity of TGF-β genes by binding to distal regulatory elements. MEG3 binding sites have GA-rich sequences, which guide MEG3 to the chromatin through RNA-DNA triplex formation. We have found that RNA-DNA triplex structures are widespread and are present over the MEG3 binding sites associated with the TGF-β pathway genes. Our findings suggest that RNA-DNA triplex formation could be a general characteristic of target gene recognition by the chromatin-interacting lncRNAs.

No MeSH data available.


Related in: MedlinePlus

Identification of repressive chromatin-associated lncRNAs usingChRIP-seq.(a) The ChRIP-seq analysis pipeline used to identify lncRNAs enrichedin repressive chromatin. The pie chart shows 276 lncRNAs enriched in bothEZH2 and H3K27me3 ChRIP-seq samples compared with the nuclear RNA (input).The P value was obtained by performing a hypergeometric test usingall the lncRNAs in our analysis. (b) Bar diagram showing thedistribution of T-to-C transitions (indicative of putativeRNA–protein contact sites) in input (8,361), EZH2 (18,905) andH3K27me3 (2,651) ChRIP-seq data. Black in the EZH2 bar indicates the numberof T-to-C transitions (1,253) that are either present in input or H3K27me3samples, and blue indicates EZH2-specific T-to-C transitions (17,652). TheEZH2-specific T-to-C transitions (17,652) were used to associate withlncRNAs. (c) All the possible conversions present in the EZH2ChRIP-seq sample. T-to-C conversion and the reverse-strand A-to-Gconversions were predominant among all the possible conversion events.(d) LncRNAs (1,046; annotated and non-annotated) harbourEZH2-specific (17,652) T-to-C conversion site. Seventy repressivechromatin-enriched lncRNAs (out of 276) carry T-to-C transitions, includingknown PRC2-interacting lncRNAs such as MEG3, KCNQ1OT1 andBDNF-AS1. The P value was obtained by performing ahypergeometric test using all the lncRNAs considered in our analysis.(e,f) The distribution of the sequencing reads on MEG3 andKCNQ1OT1 transcripts from H3K27me3, EZH2-enriched chromatinfractions and input RNA samples. The tags represent the read distributionand the signal represents the intensity of reads over MEG3 andKCNQ1OT1 transcripts. Locations of T-to-C transitions over theexons are depicted below the physical maps. The left panel depicts the RPKM(Reads per kilobase per million) for MEG3 and KCNQ1OT1 inH3K27me3, EZH2 ChRIP RNA and input RNA samples. The fold enrichment (FC) inH3K27me3 and EZH2 ChRIP RNA compared with input is indicated. (g)ChRIP validation: RT–qPCR data showing the enrichment of theselected annotated and non-annotated lncRNAs in the EZH2 and H3K27me3 ChRIPpull-downs compared with input. We did not observe any enrichment of theselncRNAs in the H3K4me2 (active chromatin marks) and immunoglobulin G (IgG;nonspecific antibody) ChRIP pull-downs. Actin was used as a negativecontrol. Data represent the mean±s.d. of three independentbiological experiments.
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f1: Identification of repressive chromatin-associated lncRNAs usingChRIP-seq.(a) The ChRIP-seq analysis pipeline used to identify lncRNAs enrichedin repressive chromatin. The pie chart shows 276 lncRNAs enriched in bothEZH2 and H3K27me3 ChRIP-seq samples compared with the nuclear RNA (input).The P value was obtained by performing a hypergeometric test usingall the lncRNAs in our analysis. (b) Bar diagram showing thedistribution of T-to-C transitions (indicative of putativeRNA–protein contact sites) in input (8,361), EZH2 (18,905) andH3K27me3 (2,651) ChRIP-seq data. Black in the EZH2 bar indicates the numberof T-to-C transitions (1,253) that are either present in input or H3K27me3samples, and blue indicates EZH2-specific T-to-C transitions (17,652). TheEZH2-specific T-to-C transitions (17,652) were used to associate withlncRNAs. (c) All the possible conversions present in the EZH2ChRIP-seq sample. T-to-C conversion and the reverse-strand A-to-Gconversions were predominant among all the possible conversion events.(d) LncRNAs (1,046; annotated and non-annotated) harbourEZH2-specific (17,652) T-to-C conversion site. Seventy repressivechromatin-enriched lncRNAs (out of 276) carry T-to-C transitions, includingknown PRC2-interacting lncRNAs such as MEG3, KCNQ1OT1 andBDNF-AS1. The P value was obtained by performing ahypergeometric test using all the lncRNAs considered in our analysis.(e,f) The distribution of the sequencing reads on MEG3 andKCNQ1OT1 transcripts from H3K27me3, EZH2-enriched chromatinfractions and input RNA samples. The tags represent the read distributionand the signal represents the intensity of reads over MEG3 andKCNQ1OT1 transcripts. Locations of T-to-C transitions over theexons are depicted below the physical maps. The left panel depicts the RPKM(Reads per kilobase per million) for MEG3 and KCNQ1OT1 inH3K27me3, EZH2 ChRIP RNA and input RNA samples. The fold enrichment (FC) inH3K27me3 and EZH2 ChRIP RNA compared with input is indicated. (g)ChRIP validation: RT–qPCR data showing the enrichment of theselected annotated and non-annotated lncRNAs in the EZH2 and H3K27me3 ChRIPpull-downs compared with input. We did not observe any enrichment of theselncRNAs in the H3K4me2 (active chromatin marks) and immunoglobulin G (IgG;nonspecific antibody) ChRIP pull-downs. Actin was used as a negativecontrol. Data represent the mean±s.d. of three independentbiological experiments.

Mentions: Previously, we have used ChRIP to verify the chromatin association of the mouseKcnq1ot1 antisense lncRNA10. Here we used a modifiedChRIP protocol in combination with photoactivatable ribonucleside-enhancedcrosslinking followed by high-throughput sequencing (ChRIP-seq) to identifylncRNAs that are associated with repressive chromatin on a global scale (Fig. 1a). In brief, we incubated BT-549 cells overnight(14–16 h) with 4-thiouridine (4sU), followed by a 40-minincubation with actinomycin D (ActD). ActD-treated BT-549 cells were crosslinkedwith formaldehyde, followed by ultraviolet irradiation. 4sU-incorporated RNA canbe crosslinked with proteins in vivo by ultraviolet irradiation.Crosslinking with formaldehyde ensures stabilization of thechromatin-interacting lncRNAs to the chromatin. Incubation of BT-549 cells withActD before crosslinking blocks transcription, which in turn prevents theco-transcriptional crosslinking of lncRNAs to the chromatin. The efficacy of thetranscriptional arrest by ActD was tested using short half-life mRNAC-MYC as described previously (Supplementary Fig. 1a)28. Chromatin was prepared fromthe formaldehyde and ultraviolet -crosslinked BT-549 cells, and was subjected toimmunoprecipitation using antibodies to H3K27me3 and EZH2. The specificity ofthe immunopurified chromatin was tested by quantitative PCR (qPCR) with positiveand negative controls (Supplementary Fig.1b). After reversal of crosslinking, RNA was isolated from theimmunoprecipitated chromatin. Isolated RNA was extensively treated with DNase Ito remove all traces of DNA, and verified again by qPCR (Supplementary Fig. 1b). The DNase I-treatedanti-H3K27me3 and anti-EZH2 purified RNAs along with nuclear input RNA weresubjected to high-throughput sequencing. The reconstruction of the nuclear RNAusing Cufflinks revealed previously annotated lncRNAs and also non-annotatedtranscripts. Coding potential analysis of the non-annotated transcripts foundthat they had lower coding probabilities, suggesting that they are noncodingRNAs (Supplementary Fig. 1c). Welooked for enrichment of the annotated and non-annotated transcripts in H3K27me3and EZH2 ChRIP-purified RNA fractions over nuclear input (Supplementary Data 1 and 2). We consideredlncRNAs in our ChRIP data set to be ‘repressive chromatinenriched' only if they were enriched (minimum twofold) in bothH3K27me3 and EZH2 ChRIP-purified RNA fractions compared with the nuclear input.We found a significant overlap (276 lncRNAs,P<9.9e−52, hypergeometricdistribution) between H3K27me3 and EZH2 ChRIP pull-downs (Fig.1a). The list of 276 lncRNAs enriched in repressive chromatincomprises both annotated and non-annotated transcripts (Supplementary Data 3). The 4sU incorporationprovided us with an additional advantage in our RNA sequencing data, as thepossible protein interaction sites on RNA lead to ultraviolet-induced T-to-Ctransitions. The T-to-C conversions at the putative RNA–proteincontact sites in ChRIP RNA sequencing samples were considered only if theminimum sequencing read depth over the conversions was ≥2 (read depthindicates total number of sequencing reads covered per transition)29. Using this criterion, we observed that T-to-C conversion wasoverrepresented in the EZH2 ChRIP RNA fraction in comparison with both theH3K27me3 ChRIP RNA and input RNA (Fig. 1b). We found thatthe overrepresentation of T-to-C conversion in EZH2 ChRIP data was not bychance, as the other nucleotide conversions were detected at background level inthe EZH2 ChRIP data compared with T to C (A to G also represents T-to-Cconversion in the reverse strand of RNA sequencing data; Fig.1c). We identified 17,652 T-to-C conversions that were present onlyin EZH2 ChRIP data but not in H3K27me3 and input RNA data. These T-to-Cconversions were then mapped to annotated and non-annotated transcripts,reconstructed from nuclear RNA input, revealing 1,046 lncRNAs with putativeRNA–protein contact sites. We found a significant overlap betweenthese lncRNAs and the lncRNAs that were enriched in EZH2 ChRIP and in repressivechromatin (enriched in both H3K27me3 and EZH2 ChRIPs) (Fig.1d, Supplementary Fig.1d and Supplementary Data4). The presence of EZH2 ChRIP-specific T-to-C conversion sites overthe repressive chromatin-associated lncRNAs indicates that they are eitherputative EZH2 contact sites or EZH2-associated protein contact sites over thelncRNAs. Interestingly, the 70 repressive chromatin-associated lncRNAs withT-to-C conversions contain several annotated and non-annotated (both intergenicand intronic) lncRNAs (Supplementary Data4 and Supplementary Fig.2a,b), including three known PRC2-interacting lncRNAs:KCNQ1OT1, MEG3 and BDNF-AS1 (Fig.1e,f and Supplementary Data4). Mouse orthologues Kcnq1ot1 and Gtl2 have been shownto interact with PRC2, and moreover Kcnq1ot1 has also been shown to beenriched in the mouse placental chromatin fraction102430. Wevalidated the repressive chromatin enrichment of some of the annotated lncRNAs(BDNF-AS1, MEG3, KCNQ1OT1 and LINC00422) andnon-annotated lncRNAs (intergenic CUFF.16286 and intronicCUFF.9557) using qPCR assay on ActD-treated and -untreated ChRIPmaterials (Fig. 1g and Supplementary Fig. 2c).


MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA-DNA triplex structures.

Mondal T, Subhash S, Vaid R, Enroth S, Uday S, Reinius B, Mitra S, Mohammed A, James AR, Hoberg E, Moustakas A, Gyllensten U, Jones SJ, Gustafsson CM, Sims AH, Westerlund F, Gorab E, Kanduri C - Nat Commun (2015)

Identification of repressive chromatin-associated lncRNAs usingChRIP-seq.(a) The ChRIP-seq analysis pipeline used to identify lncRNAs enrichedin repressive chromatin. The pie chart shows 276 lncRNAs enriched in bothEZH2 and H3K27me3 ChRIP-seq samples compared with the nuclear RNA (input).The P value was obtained by performing a hypergeometric test usingall the lncRNAs in our analysis. (b) Bar diagram showing thedistribution of T-to-C transitions (indicative of putativeRNA–protein contact sites) in input (8,361), EZH2 (18,905) andH3K27me3 (2,651) ChRIP-seq data. Black in the EZH2 bar indicates the numberof T-to-C transitions (1,253) that are either present in input or H3K27me3samples, and blue indicates EZH2-specific T-to-C transitions (17,652). TheEZH2-specific T-to-C transitions (17,652) were used to associate withlncRNAs. (c) All the possible conversions present in the EZH2ChRIP-seq sample. T-to-C conversion and the reverse-strand A-to-Gconversions were predominant among all the possible conversion events.(d) LncRNAs (1,046; annotated and non-annotated) harbourEZH2-specific (17,652) T-to-C conversion site. Seventy repressivechromatin-enriched lncRNAs (out of 276) carry T-to-C transitions, includingknown PRC2-interacting lncRNAs such as MEG3, KCNQ1OT1 andBDNF-AS1. The P value was obtained by performing ahypergeometric test using all the lncRNAs considered in our analysis.(e,f) The distribution of the sequencing reads on MEG3 andKCNQ1OT1 transcripts from H3K27me3, EZH2-enriched chromatinfractions and input RNA samples. The tags represent the read distributionand the signal represents the intensity of reads over MEG3 andKCNQ1OT1 transcripts. Locations of T-to-C transitions over theexons are depicted below the physical maps. The left panel depicts the RPKM(Reads per kilobase per million) for MEG3 and KCNQ1OT1 inH3K27me3, EZH2 ChRIP RNA and input RNA samples. The fold enrichment (FC) inH3K27me3 and EZH2 ChRIP RNA compared with input is indicated. (g)ChRIP validation: RT–qPCR data showing the enrichment of theselected annotated and non-annotated lncRNAs in the EZH2 and H3K27me3 ChRIPpull-downs compared with input. We did not observe any enrichment of theselncRNAs in the H3K4me2 (active chromatin marks) and immunoglobulin G (IgG;nonspecific antibody) ChRIP pull-downs. Actin was used as a negativecontrol. Data represent the mean±s.d. of three independentbiological experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525211&req=5

f1: Identification of repressive chromatin-associated lncRNAs usingChRIP-seq.(a) The ChRIP-seq analysis pipeline used to identify lncRNAs enrichedin repressive chromatin. The pie chart shows 276 lncRNAs enriched in bothEZH2 and H3K27me3 ChRIP-seq samples compared with the nuclear RNA (input).The P value was obtained by performing a hypergeometric test usingall the lncRNAs in our analysis. (b) Bar diagram showing thedistribution of T-to-C transitions (indicative of putativeRNA–protein contact sites) in input (8,361), EZH2 (18,905) andH3K27me3 (2,651) ChRIP-seq data. Black in the EZH2 bar indicates the numberof T-to-C transitions (1,253) that are either present in input or H3K27me3samples, and blue indicates EZH2-specific T-to-C transitions (17,652). TheEZH2-specific T-to-C transitions (17,652) were used to associate withlncRNAs. (c) All the possible conversions present in the EZH2ChRIP-seq sample. T-to-C conversion and the reverse-strand A-to-Gconversions were predominant among all the possible conversion events.(d) LncRNAs (1,046; annotated and non-annotated) harbourEZH2-specific (17,652) T-to-C conversion site. Seventy repressivechromatin-enriched lncRNAs (out of 276) carry T-to-C transitions, includingknown PRC2-interacting lncRNAs such as MEG3, KCNQ1OT1 andBDNF-AS1. The P value was obtained by performing ahypergeometric test using all the lncRNAs considered in our analysis.(e,f) The distribution of the sequencing reads on MEG3 andKCNQ1OT1 transcripts from H3K27me3, EZH2-enriched chromatinfractions and input RNA samples. The tags represent the read distributionand the signal represents the intensity of reads over MEG3 andKCNQ1OT1 transcripts. Locations of T-to-C transitions over theexons are depicted below the physical maps. The left panel depicts the RPKM(Reads per kilobase per million) for MEG3 and KCNQ1OT1 inH3K27me3, EZH2 ChRIP RNA and input RNA samples. The fold enrichment (FC) inH3K27me3 and EZH2 ChRIP RNA compared with input is indicated. (g)ChRIP validation: RT–qPCR data showing the enrichment of theselected annotated and non-annotated lncRNAs in the EZH2 and H3K27me3 ChRIPpull-downs compared with input. We did not observe any enrichment of theselncRNAs in the H3K4me2 (active chromatin marks) and immunoglobulin G (IgG;nonspecific antibody) ChRIP pull-downs. Actin was used as a negativecontrol. Data represent the mean±s.d. of three independentbiological experiments.
Mentions: Previously, we have used ChRIP to verify the chromatin association of the mouseKcnq1ot1 antisense lncRNA10. Here we used a modifiedChRIP protocol in combination with photoactivatable ribonucleside-enhancedcrosslinking followed by high-throughput sequencing (ChRIP-seq) to identifylncRNAs that are associated with repressive chromatin on a global scale (Fig. 1a). In brief, we incubated BT-549 cells overnight(14–16 h) with 4-thiouridine (4sU), followed by a 40-minincubation with actinomycin D (ActD). ActD-treated BT-549 cells were crosslinkedwith formaldehyde, followed by ultraviolet irradiation. 4sU-incorporated RNA canbe crosslinked with proteins in vivo by ultraviolet irradiation.Crosslinking with formaldehyde ensures stabilization of thechromatin-interacting lncRNAs to the chromatin. Incubation of BT-549 cells withActD before crosslinking blocks transcription, which in turn prevents theco-transcriptional crosslinking of lncRNAs to the chromatin. The efficacy of thetranscriptional arrest by ActD was tested using short half-life mRNAC-MYC as described previously (Supplementary Fig. 1a)28. Chromatin was prepared fromthe formaldehyde and ultraviolet -crosslinked BT-549 cells, and was subjected toimmunoprecipitation using antibodies to H3K27me3 and EZH2. The specificity ofthe immunopurified chromatin was tested by quantitative PCR (qPCR) with positiveand negative controls (Supplementary Fig.1b). After reversal of crosslinking, RNA was isolated from theimmunoprecipitated chromatin. Isolated RNA was extensively treated with DNase Ito remove all traces of DNA, and verified again by qPCR (Supplementary Fig. 1b). The DNase I-treatedanti-H3K27me3 and anti-EZH2 purified RNAs along with nuclear input RNA weresubjected to high-throughput sequencing. The reconstruction of the nuclear RNAusing Cufflinks revealed previously annotated lncRNAs and also non-annotatedtranscripts. Coding potential analysis of the non-annotated transcripts foundthat they had lower coding probabilities, suggesting that they are noncodingRNAs (Supplementary Fig. 1c). Welooked for enrichment of the annotated and non-annotated transcripts in H3K27me3and EZH2 ChRIP-purified RNA fractions over nuclear input (Supplementary Data 1 and 2). We consideredlncRNAs in our ChRIP data set to be ‘repressive chromatinenriched' only if they were enriched (minimum twofold) in bothH3K27me3 and EZH2 ChRIP-purified RNA fractions compared with the nuclear input.We found a significant overlap (276 lncRNAs,P<9.9e−52, hypergeometricdistribution) between H3K27me3 and EZH2 ChRIP pull-downs (Fig.1a). The list of 276 lncRNAs enriched in repressive chromatincomprises both annotated and non-annotated transcripts (Supplementary Data 3). The 4sU incorporationprovided us with an additional advantage in our RNA sequencing data, as thepossible protein interaction sites on RNA lead to ultraviolet-induced T-to-Ctransitions. The T-to-C conversions at the putative RNA–proteincontact sites in ChRIP RNA sequencing samples were considered only if theminimum sequencing read depth over the conversions was ≥2 (read depthindicates total number of sequencing reads covered per transition)29. Using this criterion, we observed that T-to-C conversion wasoverrepresented in the EZH2 ChRIP RNA fraction in comparison with both theH3K27me3 ChRIP RNA and input RNA (Fig. 1b). We found thatthe overrepresentation of T-to-C conversion in EZH2 ChRIP data was not bychance, as the other nucleotide conversions were detected at background level inthe EZH2 ChRIP data compared with T to C (A to G also represents T-to-Cconversion in the reverse strand of RNA sequencing data; Fig.1c). We identified 17,652 T-to-C conversions that were present onlyin EZH2 ChRIP data but not in H3K27me3 and input RNA data. These T-to-Cconversions were then mapped to annotated and non-annotated transcripts,reconstructed from nuclear RNA input, revealing 1,046 lncRNAs with putativeRNA–protein contact sites. We found a significant overlap betweenthese lncRNAs and the lncRNAs that were enriched in EZH2 ChRIP and in repressivechromatin (enriched in both H3K27me3 and EZH2 ChRIPs) (Fig.1d, Supplementary Fig.1d and Supplementary Data4). The presence of EZH2 ChRIP-specific T-to-C conversion sites overthe repressive chromatin-associated lncRNAs indicates that they are eitherputative EZH2 contact sites or EZH2-associated protein contact sites over thelncRNAs. Interestingly, the 70 repressive chromatin-associated lncRNAs withT-to-C conversions contain several annotated and non-annotated (both intergenicand intronic) lncRNAs (Supplementary Data4 and Supplementary Fig.2a,b), including three known PRC2-interacting lncRNAs:KCNQ1OT1, MEG3 and BDNF-AS1 (Fig.1e,f and Supplementary Data4). Mouse orthologues Kcnq1ot1 and Gtl2 have been shownto interact with PRC2, and moreover Kcnq1ot1 has also been shown to beenriched in the mouse placental chromatin fraction102430. Wevalidated the repressive chromatin enrichment of some of the annotated lncRNAs(BDNF-AS1, MEG3, KCNQ1OT1 and LINC00422) andnon-annotated lncRNAs (intergenic CUFF.16286 and intronicCUFF.9557) using qPCR assay on ActD-treated and -untreated ChRIPmaterials (Fig. 1g and Supplementary Fig. 2c).

Bottom Line: MEG3 binding sites have GA-rich sequences, which guide MEG3 to the chromatin through RNA-DNA triplex formation.We have found that RNA-DNA triplex structures are widespread and are present over the MEG3 binding sites associated with the TGF-β pathway genes.Our findings suggest that RNA-DNA triplex formation could be a general characteristic of target gene recognition by the chromatin-interacting lncRNAs.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, Sweden.

ABSTRACT
Long noncoding RNAs (lncRNAs) regulate gene expression by association with chromatin, but how they target chromatin remains poorly understood. We have used chromatin RNA immunoprecipitation-coupled high-throughput sequencing to identify 276 lncRNAs enriched in repressive chromatin from breast cancer cells. Using one of the chromatin-interacting lncRNAs, MEG3, we explore the mechanisms by which lncRNAs target chromatin. Here we show that MEG3 and EZH2 share common target genes, including the TGF-β pathway genes. Genome-wide mapping of MEG3 binding sites reveals that MEG3 modulates the activity of TGF-β genes by binding to distal regulatory elements. MEG3 binding sites have GA-rich sequences, which guide MEG3 to the chromatin through RNA-DNA triplex formation. We have found that RNA-DNA triplex structures are widespread and are present over the MEG3 binding sites associated with the TGF-β pathway genes. Our findings suggest that RNA-DNA triplex formation could be a general characteristic of target gene recognition by the chromatin-interacting lncRNAs.

No MeSH data available.


Related in: MedlinePlus