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: 41.46). 03/2011; 472(7341):120-4. DOI: 10.1038/nature09819
Source: PubMed


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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    • "Different interaction profiles also depend on the transcriptional activity of the HOX gene. In fibroblasts, chromatin loop occurs in the 5' HOX locus, where the locus is transcriptionally active, but there are no longrange chromatin interactions within the transcriptionally silent 3′ HOX (Wang et al., 2011). "
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    • "lncRNA-dependent gene activation through physical association with TrxG components While lncRNA interactions with PRC2 have been a prominent topic of investigation, it is becoming clearer that TrxG components can also physically associate with lncRNAs to regulate gene expression (Fig. 1B) (Cabianca et al., 2012; Gomez et al., 2013; Wang et al., 2011; Yang et al., 2014). One of the first and perhaps best-described examples of this comes from studies by the Chang lab looking at the vertebrate HOXA locus, which produces the long intergenic noncoding RNA (lincRNA) HOTTIP (Wang et al., 2011; Yang et al., 2014). They showed that HOTTIP is expressed from the 5′ edge of the HOXA locus and inferred that HOTTIP might be conserved because a similar lincRNA could be found in human, mouse and chick. "
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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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