Long non-coding RNAs: spatial amplifiers that control nuclear structure and gene expression

Engreitz, Jesse M.; Ollikainen, Noah; Guttman, Mitchell

doi:10.1038/nrm.2016.126

Cited by 510 publications

(437 citation statements)

References 175 publications

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“…Studies have shown that lncRNAs interact with proteins using specific domains (Engreitz et al 2016) and serve as scaffolds that govern the function of different transcription regulatory complexes. LncRNAs, while acting as scaffolds, localize to specific DNA sites while transporting the regulatory complexes to appropriate genomic locations (Chu et al 2011;Grote and Herrmann 2013;Engreitz et al 2016;Long et al 2016).…”

Section: Introductionmentioning

confidence: 99%

“…LncRNAs, while acting as scaffolds, localize to specific DNA sites while transporting the regulatory complexes to appropriate genomic locations (Chu et al 2011;Grote and Herrmann 2013;Engreitz et al 2016;Long et al 2016). Separate studies on lncRNAs (such as Fendrr and Tug1) have indicated that they localize at various genomic regions by forming a RNA:DNA:DNA triplex.…”

Section: Introductionmentioning

confidence: 99%

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Super-lncRNAs: identification of lncRNAs that target super-enhancers via RNA:DNA:DNA triplex formation

Soibam

2017

RNA

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Super-enhancers are characterized by high levels of Mediator binding and are major contributors to the expression of their associated genes. They exhibit high levels of local chromatin interactions and a higher order of local chromatin organization. On the other hand, lncRNAs can localize to specific DNA sites by forming a RNA:DNA:DNA triplex, which in turn can contribute to local chromatin organization. In this paper, we characterize a new class of lncRNAs called super-lncRNAs that target super-enhancers and which can contribute to the local chromatin organization of the super-enhancers. Using a logistic regression model based on the number of RNA:DNA:DNA triplex sites a lncRNA forms within the super-enhancer, we identify 442 unique super-lncRNA transcripts in 27 different human cell and tissue types; 70% of these super-lncRNAs were tissue restricted. They primarily harbor a single triplex-forming repeat domain, which forms an RNA:DNA:DNA triplex with multiple anchor DNA sites (originating from transposable elements) within the super-enhancers. Super-lncRNAs can be grouped into 17 different clusters based on the tissue or cell lines they target. Super-lncRNAs in a particular cluster share common short structural motifs and their corresponding super-enhancer targets are associated with gene ontology terms pertaining to the tissue or cell line. Super-lncRNAs may use these structural motifs to recruit and transport necessary regulators (such as transcription factors and Mediator complexes) to super-enhancers, influence chromatin organization, and act as spatial amplifiers for key tissue-specific genes associated with super-enhancers.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Super-lncRNAs: identification of lncRNAs that target super-enhancers via RNA:DNA:DNA triplex formation

Soibam

2017

RNA

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“…Through the use of these molecular tools, these studies have defined the functional mechanism of Xist, which has now been established as a common modality for a subclass of lncRNAs [5,25]. From the same Xic locus, Tsix emerges as a long anti-sense transcript that negatively regulates XCI.…”

Section: Rna-seqmentioning

confidence: 99%

The emerging molecular biology toolbox for the study of long noncoding RNA biology

et al. 2017

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Long noncoding RNAs (lncRNAs) have been implicated in many biological processes. However, due to the unique nature of lncRNAs and the consequential difficulties associated with their characterization, there is a growing disparity between the rate at which lncRNAs are being discovered and the assignment of biological function to these transcripts. Here we present a molecular biology toolbox equipped to help dissect aspects of lncRNA biology and reveal functionality. We outline an approach that begins with a broad survey of genome-wide, high-throughput datasets to identify potential lncRNA candidates and then narrow the focus on specific methods that are well suited to interrogate the transcripts of interest more closely. This involves the use of imaging-based strategies to validate these candidates and observe the behaviors of these transcripts at single molecule resolution in individual cells. We also describe the use of gene editing tools and interactome capture techniques to interrogate functionality and infer mechanism, respectively. With the emergence of lncRNAs as important molecules in healthy and diseased cellular function, it remains crucial to deepen our understanding of their biology. One of the greatest challenges in modern day genomics is ascribing function to genes and genetic elements. It has become apparent that most of the human genome is pervasively transcribed, but less than 2% of these outputs are putatively functional RNAs that encode for proteins [1][2][3][4]. The functions of the remaining proportion of the transcriptome and the genomic regions from which they arise, mostly remain uncharacterized and make up the 'dark matter' of the genome. With the advent and development of RNA deep sequencing technologies, long noncoding RNAs (lncRNAs) have been revealed to emanate from these dark regions of the genome [5]. For a long time, the biological utility of these transcripts remained unknown and highly controversial, with many believing that they were functionless due to their lack of any protein-coding potential. In short, they were thought to simply be the result of transcriptional noise. This skepticism was further compounded by evidence pointing to the poor specificity of RNA PolII binding and transcription initiation, their low abundance and poor conservation [6][7][8]. However, over the last decade, several examples of well-studied lncRNAs have been identified that show they are indeed functional molecules and play important roles in many biological processes [5].LncRNAs are generally products of RNA PolII activity and are arbitrarily defined as being greater than 200 nucleotides in length [9]. These transcripts can arise from genomic regions that intervene (lincRNAs) or are within protein-coding genes (i.e., introns, overlapping exons, antisense transcripts) as well as enhancer regions and promoter regions [5]. Nascent lncRNA transcripts undergo post-transcriptional modifications resulting in products that are capped at the 5 -end and often spliced and polyadenylated [9]. Furthermore, cert...

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“…The heterogeneity in the biogenesis, expression levels, stability and evolution of this diverse class of molecules reflects the broad array of functions performed by lncRNAs in the cell. Based on animal studies, lncRNAs have emerged as novel factors regulating different aspects of gene expression, and these factors have been shown to participate in transcriptional silencing by recruiting chromatin remodeling complexes [2]. Several lines of evidence suggest that lncRNAs play a role in establishing and maintaining the architecture of nuclear compartments [2].…”

Section: Introductionmentioning

confidence: 99%

A stable tRNA-like molecule is generated from the long noncoding RNA GUT15 in Arabidopsis

et al. 2018

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The Arabidopsis GUT15 RNA belongs to a class of noncoding RNAs that are expressed from the intergenic regions of protein-coding genes. We show that the RNA polymerase II transcribed GUT15 transcript serves as a precursor for two stable RNA species, a tRNA-like molecule and GUT15-tRF-F5, which are both encoded by the final intron in the GUT15 gene. The GUT15-encoded tRNA-like molecule cannot be autonomously transcribed by RNA polymerase III. However, this molecule contains a CCA motif, suggesting that it may enter the tRNA maturation pathway. The GUT15-encoded tRNA-like sequence has an inhibiting effect on the splicing of its host intron. Moreover, we demonstrate that the canonical tRNA genes nested within introns do not affect the splicing patterns of their host protein-coding transcripts.

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Long non-coding RNAs: spatial amplifiers that control nuclear structure and gene expression

Cited by 510 publications

References 175 publications

Super-lncRNAs: identification of lncRNAs that target super-enhancers via RNA:DNA:DNA triplex formation

Super-lncRNAs: identification of lncRNAs that target super-enhancers via RNA:DNA:DNA triplex formation

The emerging molecular biology toolbox for the study of long noncoding RNA biology

A stable tRNA-like molecule is generated from the long noncoding RNA GUT15 in Arabidopsis

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