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194
lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 2011
"... and differentiation ..."
Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis.
- Nature
, 2010
"... Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome 1-3 yet their potential involvement in human disease is not well understood We hybridized RNA derived from normal human breast epithelia, primary breast carcinomas, and distant metastases to ultra-dense HOX tili ..."
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Cited by 81 (1 self)
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Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome 1-3 yet their potential involvement in human disease is not well understood We hybridized RNA derived from normal human breast epithelia, primary breast carcinomas, and distant metastases to ultra-dense HOX tiling arrays 7 Quantitative PCR showed that HOTAIR is overexpressed from hundreds to nearly two-thousand-fold in breast cancer metastases, and the HOTAIR expression level is sometimes high but heterogeneous among primary tumours We next examined the effects of manipulating HOTAIR level in several breast cancer cell lines. HOTAIR levels in cell lines are significantly lower than those seen in primary or metastatic breast tumours To quantify further metastatic potential in vivo, we performed tail vein xenografts and compared the rates of lung colonization. Vector expression in the non-metastatic cell line SK-BR3 never showed lung colonization after tail vein xenograft (0 out of 15 mice), but HOTAIR
JL: Large non-coding RNAs: missing links in cancer
- Hum Mol Genet
"... Cellular homeostasis is achieved by the proper balance of regulatory networks that if disrupted can lead to cellular transformation. These cell circuits are fine-tuned and maintained by the coordinated function of pro-teins and non-coding RNAs (ncRNAs). In addition to the well-characterized protein ..."
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Cited by 26 (4 self)
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Cellular homeostasis is achieved by the proper balance of regulatory networks that if disrupted can lead to cellular transformation. These cell circuits are fine-tuned and maintained by the coordinated function of pro-teins and non-coding RNAs (ncRNAs). In addition to the well-characterized protein coding and microRNAs constituents, large ncRNAs are also emerging as important regulatory molecules in tumor-suppressor and oncogenic pathways. Recent studies have revealed mechanistic insight of large ncRNAs regulating key cancer pathways at a transcriptional, post-transcriptional and epigenetic level. Here we synthesize these latest advances within the context of their mechanistic roles in regulating and maintaining cellular equili-brium. We posit that similar to protein-coding genes, large ncRNAs are a newly emerging class of oncogenic and tumor-suppressor genes. Our growing knowledge of the role of large ncRNAs in cellular transformation is pointing towards their potential use as biomarkers and targets for novel therapeutic approaches in the future.
CpG islands - ‘a rough guide
- FEBS Lett
"... a b s t r a c t Mammalian genomes are punctuated by DNA sequences containing an atypically high frequency of CpG sites termed CpG islands (CGIs). CGIs generally lack DNA methylation and associate with the majority of annotated gene promoters. Many studies, however, have identified examples of CGI m ..."
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Cited by 20 (0 self)
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a b s t r a c t Mammalian genomes are punctuated by DNA sequences containing an atypically high frequency of CpG sites termed CpG islands (CGIs). CGIs generally lack DNA methylation and associate with the majority of annotated gene promoters. Many studies, however, have identified examples of CGI methylation in malignant cells, leading to improper gene silencing. CGI methylation also occurs in normal tissues and is known to function in X-inactivation and genomic imprinting. More recently, differential methylation has been shown between tissues, suggesting a potential role in transcriptional regulation during cell specification. Many of these tissue-specific methylated CGIs localise to regions distal to promoters, the regulatory function of which remains to be determined.
Promiscuous RNA binding by Polycomb repressive complex 2
, 2013
"... Polycomb repressive complex-2 (PRC2) is a histone methyltransferase required for epigenetic silencing during development and cancer. Long non-coding RNAs (lncRNAs) recruit PRC2 to chromatin, but the general role of RNA in maintaining repressed chromatin is unknown. Here we measure the binding consta ..."
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Cited by 16 (2 self)
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Polycomb repressive complex-2 (PRC2) is a histone methyltransferase required for epigenetic silencing during development and cancer. Long non-coding RNAs (lncRNAs) recruit PRC2 to chromatin, but the general role of RNA in maintaining repressed chromatin is unknown. Here we measure the binding constant of human PRC2 to various RNAs and find comparable affinity for human lncRNAs targeted by PRC2 and irrelevant transcripts from ciliates and bacteria. PRC2 binding is size-dependent, with lower affinity for shorter RNAs. In vivo, PRC2 predominantly occupies repressed genes; PRC2 is also associated with active genes, but most of these are not regulated by PRC2. These findings support a model in which promiscuous binding of PRC2 to RNA transcripts allows it to scan for target genes that have escaped repression, leading to maintenance of the repressed state. Such RNAs may also provide a decoy for PRC2. Polycomb repressive complex-2 (PRC2) is a histone methyltransferase that mono-, di- and tri-methylates lysine 27 of histone H3 (H3K27me3), inducing repressed chromatin1. EZH2 is the catalytic subunit of PRC2, and SUZ12 is an essential regulatory subunit2. EED is a histone-binding subunit that binds H3K27me3-modified histone tails, resulting in increased
Integrative genomic analyses reveal clinically relevant long non- coding RNA in human cancer
"... Despite growing appreciations of the importance of long non-coding RNA (lncRNA) in normal physiology and disease, our knowledge of cancer-related lncRNA remains limited. By repurposing microarray probes, we constructed the expression profile of 10,207 lncRNA genes in approximately 1,300 tumors over ..."
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Cited by 15 (1 self)
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Despite growing appreciations of the importance of long non-coding RNA (lncRNA) in normal physiology and disease, our knowledge of cancer-related lncRNA remains limited. By repurposing microarray probes, we constructed the expression profile of 10,207 lncRNA genes in approximately 1,300 tumors over four different cancer types. Through integrative analysis of the lncRNA expression profiles with clinical outcome and somatic copy number alteration (SCNA), we identified lncRNA that are associated with cancer subtypes and clinical prognosis, and predicted those that are potential drivers of cancer progression. We validated our predictions by experimentally confirming prostate cancer cell growth dependence on two novel lncRNA. Our analysis provided a resource of clinically relevant lncRNA for development of lncRNA biomarkers and identification of lncRNA therapeutic targets. It also demonstrated the power of integrating publically available genomic datasets and clinical information for discovering disease associated lncRNA. Systematic efforts to catalogue long non-coding RNA (lncRNA) using traditional cDNA Sanger sequencing1, histone mark ChIP-seq2, 3, or RNA-seq4, 5 data revealed that the human
REVIEW Enhancers and silencers: an integrated and simple model for their function
"... Regulatory DNA elements such as enhancers, silencers and insulators are embedded in metazoan genomes, and they control gene expression during development. Although they fulfil different roles, they share specific properties. Herein we discuss some examples and a parsimonious model for their function ..."
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Cited by 9 (7 self)
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Regulatory DNA elements such as enhancers, silencers and insulators are embedded in metazoan genomes, and they control gene expression during development. Although they fulfil different roles, they share specific properties. Herein we discuss some examples and a parsimonious model for their function is proposed. All are transcription units that tether their target promoters close to, or distant from, transcriptional hot spots (or ‘factories’).
Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature. 2013; 494:497–501. [PubMed: 23417068
"... Recent advances in genomic research have revealed the existence of a large number of transcripts devoid of protein-coding potential in multiple organisms 1-8. While the functional role for long non-coding RNAs (lncRNAs) has been best defined in epigenetic phenomena such as X inactivation and imprint ..."
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Cited by 8 (0 self)
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Recent advances in genomic research have revealed the existence of a large number of transcripts devoid of protein-coding potential in multiple organisms 1-8. While the functional role for long non-coding RNAs (lncRNAs) has been best defined in epigenetic phenomena such as X inactivation and imprinting, different classes of lncRNAs may have varied biological functions 8-13. We and others have identified a class of lncRNAs, termed ncRNA-activating (ncRNA-a), that function to activate their neighboring genes using a cis-mediated mechanism 5,14-16. To define the precise mode by which such enhancer-like RNAs function, we depleted factors with known roles in transcriptional activation and assessed their role in RNA-dependent activation. Here we report that depletion of the components of the co-activator complex, Mediator, specifically and potently diminished the ncRNA-induced activation of transcription in such a heterologous reporter assay. In vivo, Mediator is recruited to ncRNA-as target genes, and regulates their expression. We show that ncRNA-as interact with Mediator to regulate its chromatin localization and kinase activity toward histone H3 serine 10. Mediator complex harboring disease causing MED12 mutations 17,18 displays diminished ability to
NPInter v2.0: an updated database of ncRNA interactions
- Nucleic Acids Res
, 2014
"... NPInter ..."
