Article

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, Jul 07, 2015
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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 (http://splicemap.bioinf.uni-leipzig.de) 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 http://www.bioinf.uni-leipzig.de/publications/supplements/12-001. © 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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    • "The fact that 3C ligation products originate mainly from insoluble aggregates within unlysed swollen nuclei rather than on soluble chromatin (Gavrilov et al. 2013c) raises the possibility that nuclear structures enhance or promote 3C associations, as was suggested for the active b-globin gene and its enhancer (Gavrilov et al. 2013a). This may also explain why higher 3C contact frequencies and inferred structurally compact domains were previously found associated with activated Hox loci in human fibroblasts (Wang et al. 2011) and mouse embryos (Noordermeer et al. 2011, 2014). "
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    ABSTRACT: Although important for gene regulation, most studies of genome organization use either fluorescence in situ hybridization (FISH) or chromosome conformation capture (3C) methods. FISH directly visualizes the spatial relationship of sequences but is usually applied to a few loci at a time. The frequency at which sequences are ligated together by formaldehyde cross-linking can be measured genome-wide by 3C methods, with higher frequencies thought to reflect shorter distances. FISH and 3C should therefore give the same views of genome organization, but this has not been tested extensively. We investigated the murine HoxD locus with 3C carbon copy (5C) and FISH in different developmental and activity states and in the presence or absence of epigenetic regulators. We identified situations in which the two data sets are concordant but found other conditions under which chromatin topographies extrapolated from 5C or FISH data are not compatible. We suggest that products captured by 3C do not always reflect spatial proximity, with ligation occurring between sequences located hundreds of nanometers apart, influenced by nuclear environment and chromatin composition. We conclude that results obtained at high resolution with either 3C methods or FISH alone must be interpreted with caution and that views about genome organization should be validated by independent methods. © 2014 Williamson et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & Development 12/2014; 28(24):2778-2791. DOI:10.1101/gad.251694.114 · 12.64 Impact Factor