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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Available from: Kevin C Wang
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    • "The lncRNAs may directly or indirectly recruit protein complexes involved in chromosome modifications, which results in epigenetic regulation[91]. In accordance with the relative positional relationship between lncRNAs and their target genes, mechanisms by which lncRNAs regulate target genes can be considered cis8485868788or trans[83,89]. For those lncRNAs regulating target genes in cis, it was found that the RNAs can form a nuclear complex that is closely linked to the silenced genes. "

    Full-text · Article · Jan 2016 · International Journal of Molecular Sciences
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    • "For example, HOTAIR suppresses transcription of the HoxD locus in trans by targeting the polycomb-repressive complex 2 (PRC2) and the H3K4 demethylase LSD1 to this locus (Tsai et al., 2010). In the HoxA locus, two lincRNAs, HOTTIP and Mistra, control transcription of HoxA genes by recruiting MLL H3K4 histone methyltransferase (HMT) complexes (Bertani et al., 2015; Wang et al., 2011). Recent studies revealed that dozens of ESC-expressed lincRNAs maintain the ESC pluripotency by acting as regulatory circuitries of ESC gene expression programs (Guttman et al., 2011). "
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    ABSTRACT: Trithorax proteins and long-intergenic noncoding RNAs are critical regulators of embryonic stem cell pluripotency; however, how they cooperatively regulate germ layer mesoderm specification remains elusive. We report here that HoxBlinc RNA first specifies Flk1(+) mesoderm and then promotes hematopoietic differentiation through regulation of hoxb pathways. HoxBlinc binds to the hoxb genes, recruits Setd1a/MLL1 complexes, and mediates long-range chromatin interactions to activate transcription of the hoxb genes. Depletion of HoxBlinc by shRNA-mediated knockdown or CRISPR-Cas9-mediated genetic deletion inhibits expression of hoxb genes and other factors regulating cardiac/hematopoietic differentiation. Reduced hoxb expression is accompanied by decreased recruitment of Set1/MLL1 and H3K4me3 modification, as well as by reduced chromatin loop formation. Re-expression of hoxb2-b4 genes in HoxBlinc-depleted embryoid bodies rescues Flk1(+) precursors that undergo hematopoietic differentiation. Thus, HoxBlinc plays an important role in controlling hoxb transcription networks that mediate specification of mesoderm-derived Flk1(+) precursors and differentiation of Flk1(+) cells into hematopoietic lineages.
    Full-text · Article · Jan 2016 · Cell Reports
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    • "In human distal cells, the lncRNA HOTTIP recruits the histone H3K4-modifying complex MLL1 by binding to WDR5, targeting this complex to the HOXA locus. Thus, chromatin modifications together with higherorder chromosomal looping bring the HOTTIP RNA in close proximity to HOXA genes [38, 39]. In our study, the LINC00152 may be required for maintaining transcriptionally active EpCAM genes at the 5′ end of the cluster. "
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    ABSTRACT: Hepatocellular carcinoma (HCC) is well known as the sixth most common malignant tumor and the third leading cause of cancer-related deaths globally. LINC00152 was documented as an important long non-coding RNA (lncRNA) involved in the pathogenesis of gastric cancer; however, the detailed mechanism of action of LINC00152 remains unknown. Here, based on the increased level of LINC00152 in HCC tissues, we found that LINC00152 could promote cell proliferation in vitro and tumor growth in vivo. Furthermore, microarray-based analysis indicated that LINC00152 could activate the mechanistic target of rapamycin(mTOR) pathway by binding to the promoter of EpCAM through a cis-regulation, as confirmed by Gal4-λN/BoxB reporter system. Thus, LINC00152 might be involved in the oncogenesis of HCC by activating the mTOR signaling pathway and might be a novel index for clinical diagnosis in the future.
    Preview · Article · Nov 2015 · Oncotarget
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