A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression

Howard Hughes Medical Institute, Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature (Impact Factor: 42.35). 03/2011; 472(7341):120-4. DOI: 10.1038/nature09819
Source: PubMed

ABSTRACT The genome is extensively transcribed into long intergenic noncoding RNAs (lincRNAs), many of which are implicated in gene silencing. Potential roles of lincRNAs in gene activation are much less understood. Development and homeostasis require coordinate regulation of neighbouring genes through a process termed locus control. Some locus control elements and enhancers transcribe lincRNAs, hinting at possible roles in long-range control. In vertebrates, 39 Hox genes, encoding homeodomain transcription factors critical for positional identity, are clustered in four chromosomal loci; the Hox genes are expressed in nested anterior-posterior and proximal-distal patterns colinear with their genomic position from 3' to 5'of the cluster. Here we identify HOTTIP, a lincRNA transcribed from the 5' tip of the HOXA locus that coordinates the activation of several 5' HOXA genes in vivo. Chromosomal looping brings HOTTIP into close proximity to its target genes. HOTTIP RNA binds the adaptor protein WDR5 directly and targets WDR5/MLL complexes across HOXA, driving histone H3 lysine 4 trimethylation and gene transcription. Induced proximity is necessary and sufficient for HOTTIP RNA activation of its target genes. Thus, by serving as key intermediates that transmit information from higher order chromosomal looping into chromatin modifications, lincRNAs may organize chromatin domains to coordinate long-range gene activation.

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Available from: Kevin C Wang, Aug 19, 2015
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    • "We find that the majority of known lncRNAs are chromatin enriched , extending this property from the small set of well-studied lncRNAs (Chalei et al., 2014; Mohammad et al., 2010; Nagano et al., 2008; Rinn et al., 2007; Wang et al., 2011b) to a more general principle, thereby providing a resource for future mechanistic studies (Table S1). We also observe that trans-acting lncRNAs exhibit intermediate levels of chromatin enrichment, suggesting either more labile chromatin attachment or reflecting two distinct pools of molecules: those bound to or searching for their target loci (Bond et al., 2009; Rinn et al., 2007). "
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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; DOI:10.1016/j.celrep.2015.07.033 · 8.36 Impact Factor
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    • "In contrast, the lncRNA HOTTIP (HOXA transcript at the distal tip) mediates transcriptional activation by controlling chromatin modification and organization (Wang et al., 2011). HOTTIP is produced from the 5'-end of the HOXA locus, downstream of HOXA13. "
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    ABSTRACT: Long non-coding RNAs (lncRNAs) are transcripts without protein-coding potential but having a pivotal role in numerous biological functions. Long non-coding RNAs act as regulators at different levels of gene expression including chromatin organization, transcriptional regulation and post-transcriptional control. Misregulation of lncRNAs expression has been found to be associated to cancer and other human disorders. Here, we review the different types of lncRNAs, their mechanisms of action on genome formatting and expression and emphasized on the multifaceted action of the H19 lncRNA.
    Frontiers in Genetics 04/2015; 6. DOI:10.3389/fgene.2015.00165
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    • "The HOX clusters may serve as a particularly impressive example. On the one hand, many well-characterized mRNA-like lncRNAs (Mainguy et al. 2007; Rinn et al. 2007), including HOTAIR (Rinn et al. 2007; Tsai et al. 2010), HOTTIP (Wang et al. 2011), and several microRNA precursors (Tanzer et al. 2005), are transcribed from the intergenic regions, on the other hand, the region is packed with conserved functional DNA elements (Lee et al. 2006; Punnamoottil et al. 2010; Natale et al. 2011). The observable conservation of genomic sequence thus does not in itself provide sufficient information to disentangle the evolutionary history of lncRNAs. "
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    ABSTRACT: Large-scale RNA sequencing has revealed a large number of long mRNA-like transcripts (lncRNAs) that do not code for proteins. The evolutionary history of these lncRNAs has been notoriously hard to study systematically due to their low level of sequence conservation that precludes comprehensive homology-based surveys and makes them nearly impossible to align. An increasing number of special cases, however, has been shown to be at least as old as the vertebrate lineage. Here we use the conservation of splice sites to trace the evolution of lncRNAs. We show that >85% of the human GENCODE lncRNAs were already present at the divergence of placental mammals and many hundreds of these RNAs date back even further. Nevertheless, we observe a fast turnover of intron/exon structures. We conclude that lncRNA genes are evolutionary ancient components of vertebrate genomes that show an unexpected and unprecedented evolutionary plasticity. We offer a public web service ( that allows to retrieve sets of orthologous splice sites and to produce overview maps of evolutionarily conserved splice sites for visualization and further analysis. An electronic supplement containing the ncRNA data sets used in this study is available at © 2015 Nitsche et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.
    RNA 03/2015; 21(5). DOI:10.1261/rna.046342.114 · 4.62 Impact Factor
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