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Concept: Long noncoding RNA

172

A report on the Keystone symposium ‘Non-coding RNAs’ held at Snowbird, Utah, USA, 31 March to 5 April 2012.

Concepts: DNA, RNA, Non-coding RNA, Transfer RNA, Long noncoding RNA, Xist

171

Recent genome-wide computational screens that search for conservation of RNA secondary structure in whole genome alignments (WGAs) have predicted thousands of structural noncoding RNAs (ncRNAs). The sensitivity of such approaches, however, is limited due to their reliance on sequence-based whole-genome aligners, which regularly misalign structural ncRNAs. This suggests that many more structural ncRNAs may remain undetected. Structure-based alignment, which could increase the sensitivity, has been prohibitive for genome-wide screens due to its extreme computational costs. Breaking this barrier, we present the pipeline REAPR (RE-Alignment for Prediction of structural ncRNA), which efficiently realigns whole genomes based on RNA sequence and structure, thus allowing us to boost the performance of de novo ncRNA predictors, such as RNAz. Key to the pipeline’s efficiency is the development of a novel banding technique for multiple RNA alignment. REAPR significantly outperforms the widely-used predictors RNAz and EvoFold in genome-wide screens; in direct comparison to the most recent RNAz screen on D. melanogaster, REAPR predicts twice as many high-confidence ncRNA candidates. Moreover, modEncode RNA-Seq experiments confirm a substantial number of its predictions as transcripts. REAPR’s advancement of de novo structural characterization of ncRNAs complements the identification of transcripts from rapidly accumulating RNA-Seq data.

Concepts: DNA, Gene, Genome, RNA, Prediction, Non-coding RNA, Transfer RNA, Long noncoding RNA

152

Although the chemopreventive effects of aspirin have been extensively investigated, the roles of many cell components, such as long non-coding RNAs, in these effects are still not completely understood.

Concepts: DNA, RNA, Ribosomal RNA, Non-coding RNA, RNA splicing, Transfer RNA, Long noncoding RNA, Xist

33

Recent studies have implicated long noncoding RNAs (lncRNAs) as regulators of many important biological processes. Here we report on the identification and characterization of a lncRNA, lnc13, that harbors a celiac disease-associated haplotype block and represses expression of certain inflammatory genes under homeostatic conditions. Lnc13 regulates gene expression by binding to hnRNPD, a member of a family of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). Upon stimulation, lnc13 levels are reduced, thereby allowing increased expression of the repressed genes. Lnc13 levels are significantly decreased in small intestinal biopsy samples from patients with celiac disease, which suggests that down-regulation of lnc13 may contribute to the inflammation seen in this disease. Furthermore, the lnc13 disease-associated variant binds hnRNPD less efficiently than its wild-type counterpart, thus helping to explain how these single-nucleotide polymorphisms contribute to celiac disease.

Concepts: DNA, Gene, Genetics, Gene expression, Molecular biology, RNA, Non-coding RNA, Long noncoding RNA

32

The human genome produces thousands of long noncoding RNAs (lncRNAs) - transcripts >200 nucleotides long that do not encode proteins. While critical roles in normal biology and disease have been revealed for a subset of lncRNAs, the function of the vast majority remains untested. Here, we developed a CRISPR interference (CRISPRi) platform targeting 16,401 lncRNA loci in 7 diverse cell lines including 6 transformed cell lines and human induced pluripotent stem cells (iPSCs). Large-scale screening identified 499 lncRNA loci required for robust cellular growth, of which 89% showed growth modifying function exclusively in one cell type. We further found that lncRNA knockdown can perturb complex transcriptional networks in a cell type-specific manner. These data underscore the functional importance and cell type-specificity of many lncRNAs.

Concepts: DNA, Protein, Gene, Genetics, RNA, Stem cell, Cell biology, Long noncoding RNA

28

Despite improvement in our understanding of long noncoding RNAs (lncRNAs) role in cancer, efforts to find clinically relevant cancer-associated lncRNAs are still lacking. Here, using nascent RNA capture sequencing, we identify 1145 temporally expressed S-phase-enriched lncRNAs. Among these, 570 lncRNAs show significant differential expression in at least one tumor type across TCGA data sets. Systematic clinical investigation of 14 Pan-Cancer data sets identified 633 independent prognostic markers. Silencing of the top differentially expressed and clinically relevant S-phase-enriched lncRNAs in several cancer models affects crucial cancer cell hallmarks. Mechanistic investigations on SCAT7 in multiple cancer types reveal that it interacts with hnRNPK/YBX1 complex and affects cancer cell hallmarks through the regulation of FGF/FGFR and its downstream PI3K/AKT and MAPK pathways. We also implement a LNA-antisense oligo-based strategy to treat cancer cell line and patient-derived tumor (PDX) xenografts. Thus, this study provides a comprehensive list of lncRNA-based oncogenic drivers with potential prognostic value.

Concepts: DNA, Gene, Gene expression, Cancer, Oncology, Lung cancer, Oncogene, Long noncoding RNA

28

SUMMARY: ncPRO-seq (Non-Coding RNA PROfiling in sRNA-seq) is a stand-alone, comprehensive and flexible ncRNA analysis pipeline. It can interrogate and perform detailed profiling analysis on small RNAs derived from annotated non-coding regions in miRBase, Rfam and RepeatMasker, as well as specific regions defined by users. The ncPRO-seq pipeline performs both gene-based and family-based analyses of small RNAs. It also has a module to identify regions significantly enriched with short reads, that cannot be classified under known ncRNA families, thus enabling the discovery of previously unknown ncRNA- or siRNA-producing regions. The ncPRO-seq pipeline supports input read sequences in fastq, fasta and color space format, as well as alignment results in BAM format, meaning that small RNA raw data from the 3 current major platforms (Roche-454, Illumina-Solexa and Life technologies-SOLiD) can be analyzed with this pipeline. The ncPRO-seq pipeline can be used to analyze read and alignment data, based on any sequenced genome, including, mammals and plants. AVAILABILITY: source code, annotation files, manual and online version are available at http://ncpro.curie.fr/. CONTACT: bioinfo.ncproseq@curie.fr; cciaudo@ethz.chSupplementary information Supplementary data are available at Bioinformatics online.

Concepts: DNA, RNA, Ribosomal RNA, Small interfering RNA, Non-coding RNA, Transfer RNA, Long noncoding RNA, Xist

27

Non-coding RNAs, especially small RNAs, play important roles in many biological processes. Several small RNA types, including microRNAs (miRNAs) and small interfering RNAs (siRNAs), are well-described in rice (Oryza sativa), although much remains to be learned about their function. Many small RNAs along with their targets have been characterized with deep sequencing technologies. Some special classes of these small RNAs have been found to be unique to rice or within the larger group of grasses. The functional and biological roles of numerous plants small RNAs have been described in detail, including functions as varied as the regulation of tissue development, phase transition, or abiotic and biotic stress resistance. Mutant analysis has proven useful in the genetic identification of components involved in small RNA biogenesis and also in identification of regulatory functions of small RNAs. Although many small RNAs have been identified by deep sequencing in rice, their precise regulatory functions and cell-type specificity are in many cases still unknown.

Concepts: DNA, Gene, RNA, Small interfering RNA, Non-coding RNA, Transfer RNA, Long noncoding RNA, Xist

27

Long noncoding RNAs (lncRNAs) are key regulators of diverse biological processes such as transcriptional regulation, cell growth and differentiation. Previous studies have demonstrated that the lncRNA-ANCR (anti-differentiation ncRNA) is required to maintain the undifferentiated cell state within the epidermis. However, little is known about whether ANCR regulates osteoblast differentiation. In this study, we found that the ANCR expression level is significantly decreased during hFOB1.19 cell differentiation. ANCR-siRNA blocks the expression of endogenous ANCR, resulting in osteoblast differentiation, whereas ANCR overexpression is sufficient to inhibit osteoblast differentiation. We further demonstrated that ANCR is associated with enhancer of zeste homolog 2 (EZH2) and that this association results in the inhibition of both Runx2 expression and subsequent osteoblast differentiation. These data suggest that ANCR is an essential mediator of osteoblast differentiation, thus offering a new target for the development of therapeutic agents to treat bone diseases.

Concepts: DNA, Gene, Gene expression, Developmental biology, Bone marrow, Regulation of gene expression, Cellular differentiation, Long noncoding RNA

26

We here highlight recent studies that in vivo demonstrate an involvement of microRNAs in atherosclerotic lesion formation and provide important preclinical evidence of their therapeutic targeting in atherosclerosis, with a particular focus on endothelial cells and macrophages. We also briefly discuss the emerging role of long noncoding RNAs herein.

Concepts: Inflammation, Monocyte, Gene, Atherosclerosis, Macrophage, Blood vessel, Endothelium, Long noncoding RNA