Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins.
TL;DR: The initial functional analysis of a poorly characterized human lncRNA that is induced after DNA damage is described, introducing a mechanism that regulates the activity of a deeply conserved and highly dosage-sensitive family of RNA binding proteins and reveal unanticipated roles for a lnc RNA and PUMILIO proteins in the maintenance of genomic stability.
About: This article is published in Cell.The article was published on 2016-01-14 and is currently open access. It has received 648 citations till now. The article focuses on the topics: Non-coding RNA & PUM1.
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TL;DR: It is understood that lncRNAs drive many important cancer phenotypes through their interactions with other cellular macromolecules including DNA, protein, and RNA, making these molecules attractive targets for therapeutic intervention in the fight against cancer.
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TL;DR: This review categorizes lncRNA loci into those that regulate gene expression in cis versus those that perform functions in trans and proposes an experimental approach to dissect lncRNAs activity based on these classifications.
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Cites background from "Noncoding RNA NORAD Regulates Genom..."
...The sequence of NORAD contains 5 repeated units of 500 nt each, termed NORAD domains (Lee et al., 2016), and can be further divided into 12 shorter repeating sequences (Tichon et al., 2016)....
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..., 2015), as have lncRNAs whose expression is differentially regulated under diverse stress conditions or after activation of signaling pathways (Atianand et al., 2016; Lee et al., 2016; Michalik et al., 2014)....
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...Interestingly, either overexpression or deletion of PUM1/ PUM2 in mammalian cell lines resulted in aneuploidy, indicating that PUMILIO activity must be maintained within a narrow range to avoid deleterious consequences....
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...The lncRNA NORAD (noncoding RNA activated by DNA damage), functions as a molecular decoy for the RNA-binding proteins PUMILIO1 (PUM1) and PUMILIO2 (PUM2) (Lee et al., 2016; Tichon et al., 2016) (Figure 2C)....
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...PUMILIO targets are highly enriched for regulators of mitosis, and their repression results in chromosomal instability and aneuploidy in NORAD knockout cells (Lee et al., 2016)....
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TL;DR: A review of the mechanisms of lncRNA biogenesis, localization and functions in transcriptional, post-transcriptional and other modes of gene regulation, and their potential therapeutic applications is presented in this article.
Abstract: Evidence accumulated over the past decade shows that long non-coding RNAs (lncRNAs) are widely expressed and have key roles in gene regulation. Recent studies have begun to unravel how the biogenesis of lncRNAs is distinct from that of mRNAs and is linked with their specific subcellular localizations and functions. Depending on their localization and their specific interactions with DNA, RNA and proteins, lncRNAs can modulate chromatin function, regulate the assembly and function of membraneless nuclear bodies, alter the stability and translation of cytoplasmic mRNAs and interfere with signalling pathways. Many of these functions ultimately affect gene expression in diverse biological and physiopathological contexts, such as in neuronal disorders, immune responses and cancer. Tissue-specific and condition-specific expression patterns suggest that lncRNAs are potential biomarkers and provide a rationale to target them clinically. In this Review, we discuss the mechanisms of lncRNA biogenesis, localization and functions in transcriptional, post-transcriptional and other modes of gene regulation, and their potential therapeutic applications.
1,630 citations
Benjamin J. Raphael, Ralph H. Hruban, Andrew J. Aguirre, Richard A. Moffitt +262 more•Institutions (1)
TL;DR: An integrated multi-platform analysis of 150 pancreatic ductal adenocarcinoma specimens reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.
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TL;DR: Long noncoding RNAs (lncRNAs) are emerging as important regulators in gene expression networks by controlling nuclear architecture and transcription in the nucleus and by modulating mRNA stability, translation and post-translational modifications in the cytoplasm as mentioned in this paper.
Abstract: A diverse catalog of long noncoding RNAs (lncRNAs), which lack protein-coding potential, are transcribed from the mammalian genome. They are emerging as important regulators in gene expression networks by controlling nuclear architecture and transcription in the nucleus and by modulating mRNA stability, translation and post-translational modifications in the cytoplasm. In this Review, we highlight recent progress in cellular functions of lncRNAs at the molecular level in mammalian cells.
904 citations
References
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TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
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TL;DR: The Gene Set Enrichment Analysis (GSEA) method as discussed by the authors focuses on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation.
Abstract: Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.
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TL;DR: EdgeR as mentioned in this paper is a Bioconductor software package for examining differential expression of replicated count data, which uses an overdispersed Poisson model to account for both biological and technical variability and empirical Bayes methods are used to moderate the degree of overdispersion across transcripts, improving the reliability of inference.
Abstract: Summary: It is expected that emerging digital gene expression (DGE) technologies will overtake microarray technologies in the near future for many functional genomics applications. One of the fundamental data analysis tasks, especially for gene expression studies, involves determining whether there is evidence that counts for a transcript or exon are significantly different across experimental conditions. edgeR is a Bioconductor software package for examining differential expression of replicated count data. An overdispersed Poisson model is used to account for both biological and technical variability. Empirical Bayes methods are used to moderate the degree of overdispersion across transcripts, improving the reliability of inference. The methodology can be used even with the most minimal levels of replication, provided at least one phenotype or experimental condition is replicated. The software may have other applications beyond sequencing data, such as proteome peptide count data. Availability: The package is freely available under the LGPL licence from the Bioconductor web site (http://bioconductor.org).
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TL;DR: Bowtie extends previous Burrows-Wheeler techniques with a novel quality-aware backtracking algorithm that permits mismatches and can be used simultaneously to achieve even greater alignment speeds.
Abstract: Bowtie is an ultrafast, memory-efficient alignment program for aligning short DNA sequence reads to large genomes. For the human genome, Burrows-Wheeler indexing allows Bowtie to align more than 25 million reads per CPU hour with a memory footprint of approximately 1.3 gigabytes. Bowtie extends previous Burrows-Wheeler techniques with a novel quality-aware backtracking algorithm that permits mismatches. Multiple processor cores can be used simultaneously to achieve even greater alignment speeds. Bowtie is open source http://bowtie.cbcb.umd.edu.
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TL;DR: The command-line tool cutadapt is developed, which supports 454, Illumina and SOLiD (color space) data, offers two adapter trimming algorithms, and has other useful features.
Abstract: When small RNA is sequenced on current sequencing machines, the resulting reads are usually longer than the RNA and therefore contain parts of the 3' adapter. That adapter must be found and removed error-tolerantly from each read before read mapping. Previous solutions are either hard to use or do not offer required features, in particular support for color space data. As an easy to use alternative, we developed the command-line tool cutadapt, which supports 454, Illumina and SOLiD (color space) data, offers two adapter trimming algorithms, and has other useful features. Cutadapt, including its MIT-licensed source code, is available for download at http://code.google.com/p/cutadapt/
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