Rinn, J.: Modular regulatory principles of large non-coding RNAs. Nature 482, 339-346

Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Nature (Impact Factor: 41.46). 02/2012; 482(7385):339-46. DOI: 10.1038/nature10887
Source: PubMed


It is clear that RNA has a diverse set of functions and is more than just a messenger between gene and protein. The mammalian genome is extensively transcribed, giving rise to thousands of non-coding transcripts. Whether all of these transcripts are functional is debated, but it is evident that there are many functional large non-coding RNAs (ncRNAs). Recent studies have begun to explore the functional diversity and mechanistic role of these large ncRNAs. Here we synthesize these studies to provide an emerging model whereby large ncRNAs might achieve regulatory specificity through modularity, assembling diverse combinations of proteins and possibly RNA and DNA interactions.

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    • "Although widely speculated (Bonasio et al., 2010; Guttman and Rinn, 2012; Quinodoz and Guttman, 2014; Rinn and Chang, 2012), we are not aware of tests of this proposed chromatin association beyond a few anecdotal cases (Mao et al., 2011; Simon et al., 2011). This result is consistent with the cis-activating correlation observed, leading to a model where ongoing or paused transcription of noncoding RNAs influences the expression of proximal genes (Bonasio et al., 2010; Guttman and Rinn, 2012). Conversely, the 25% of cheRNAs that remain on chromatin after pausing RNAPII transcription for 2 hr are compelling candidates for lncRNAs that may utilize additional methods of attachment (Jeon and Lee, 2011). "
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    ABSTRACT: A number of long noncoding RNAs (lncRNAs) have been reported to regulate transcription via recruitment of chromatin modifiers or bridging distal enhancer elements to gene promoters. However, the generality of these modes of regulation and the mechanisms of chromatin attachment for thousands of unstudied human lncRNAs remain unclear. To address these questions, we performed stringent nuclear fractionation coupled to RNA sequencing. We provide genome-wide identification of human chromatin-associated lncRNAs and demonstrate tethering of RNA to chromatin by RNAPII is a pervasive mechanism of attachment. We also uncovered thousands of chromatin-enriched RNAs (cheRNAs) that share molecular properties with known lncRNAs. Although distinct from eRNAs derived from active prototypical enhancers, the production of cheRNAs is strongly correlated with the expression of neighboring protein-coding genes. This work provides an updated framework for nuclear RNA organization that includes a large chromatin-associated transcript population correlated with active genes and may prove useful in de novo enhancer annotation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 08/2015; 12(7). DOI:10.1016/j.celrep.2015.07.033 · 8.36 Impact Factor
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    • "Nowadays, it is assumed that 98% of the transcribed RNA in humans is not translated into a protein (Mattick & Makunin, 2005). Previously considered to be simply transcriptional junk, these untranslated RNAs (noncoding RNAs, ncRNAs) can have catalytic activity, serve as protein scaffolds, guide the cellular machinery, and are crucial in all aspects of gene expression, such as regulating chromatin remodeling, transcription, and many posttranscriptional events, both in prokaryotes and eukaryotes (Baker, 2011; Guttman & Rinn, 2012; Mattick et al., 2005; Morris & Mattick, 2014; Ponting, Oliver, & Reik, 2009; Storz, Altuvia, & Wassarman, 2005; Wiedenheft, Sternberg, & Doudna, 2012). Some ncRNAs have 100,000 nucleotides such as the long ncRNA Air present in mammals, whereas silencing RNAs may be only 20 nucleotides long (Storz et al., 2005) and are considered as a potential new class of drugs (Fichou & Férec, 2006). "
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    ABSTRACT: Although functional significance of large noncoding RNAs and their complexes with proteins is well recognized, structural information for this class of systems is very scarce. Their inherent flexibility causes problems in crystallographic approaches, while their typical size is beyond the limits of state-of-the-art purely NMR-based approaches. Here, we review an approach that combines high-resolution NMR restraints with lower resolution long-range constraints based on site-directed spin labeling and measurements of distance distribution restraints in the range between 15 and 80Å by the four-pulse double electron-electron resonance (DEER) EPR technique. We discuss sample preparation, the basic assumptions behind data analysis in the EPR-based distance measurements, treatment of the label-based constraints in generation of the structure, and the back-calculation of distance distributions for structure validation. Step-by-step protocols are provided for DEER distance distribution measurements including data analysis and for CYANA based structure calculation using combined NMR and EPR data. © 2015 Elsevier Inc. All rights reserved.
    Methods in enzymology 06/2015; 558(1):279-331. DOI:10.1016/bs.mie.2015.02.005 · 2.09 Impact Factor
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    • "This suggests that negative selection is acting on only portions of lncRNAs or on their higher-order structure (Washietl et al. 2014). Highly conserved elements within lncRNA sequences, interspersed with longer and less conserved stretches of nucleotide sequences, have been reported (Guttman and Rinn 2012; Ulitsky and Bartel 2013). Well-known examples of such elements , which could have evolved for specific protein and/or RNA interactions, include the PRC2-binding elements in the lncRNA Xist (Maenner et al. 2010), the 26 nt miR-7 binding site in the zebrafish lncRNA Cyrano (Ulitsky et al. 2011), and the Splicing factor 1 (Sf1) binding site in the mammalian lncRNA Miat (Rapicavoli et al. 2010; Tsuiji et al. 2011). "
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    ABSTRACT: Long non-coding RNAs (lncRNAs) are important developmental regulators in bilaterian animals. A correlation has been claimed between the lncRNA repertoire expansion and morphological complexity in vertebrate evolution. However, this claim has not been tested by examining morphologically simple animals. Here, we undertake a systematic investigation of lncRNAs in the demosponge Amphimedon queenslandica, a morphologically-simple, early-branching metazoan. We combine RNA-Seq data across multiple developmental stages of Amphimedon with a filtering pipeline to conservatively predict 2,935 lncRNAs. These include intronic overlapping lncRNAs, exonic antisense overlapping lncRNAs, long intergenic ncRNAs and precursors for small RNAs. Sponge lncRNAs are remarkably similar to their bilaterian counterparts in being relatively short with few exons and having low primary sequence conservation relative to protein-coding genes. As in bilaterians, a majority of sponge lncRNAs exhibit typical hallmarks of regulatory molecules, including high temporal specificity and dynamic developmental expression. Specific lncRNA expression profiles correlate tightly with conserved protein-coding genes likely involved in a range of developmental and physiological processes, such as the Wnt signaling pathway. Although the majority of Amphimedon lncRNAs appear to be taxonomically-restricted with no identifiable orthologues, we find a few cases of conservation between demosponges in lncRNAs that are antisense to coding sequences. Based on the high similarity in the structure, organisation and dynamic expression of sponge lncRNAs to their bilaterian counterparts, we propose that these non-coding RNAs are an ancient feature of the metazoan genome. These results are consistent with lncRNAs regulating the development of animals, regardless of their level of morphological complexity.
    Molecular Biology and Evolution 05/2015; DOI:10.1093/molbev/msv117 · 9.11 Impact Factor
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