starBase Pan-Cancer Update: deciphering Pan-Cancer patterns of lncRNAs, ceRNAs, miRNAs and RNA-binding proteins from TCGA 14 cancer types

Posted by lncRNAblog on January 20th, 2014

starBase has been updated to explore Pan-Cancer pattern of lncRNAs, miRNAs, RNA-binding proteins (RBP) and their regulatory networks (ceRNA, coexpression) by mining expression profiles of miRNAs, lncRNAs and mRNAs across 14 cancer types (>6000 samples) from The Cancer Genome Atlas (TCGA) Data Portal (all data available without limitations).

starBase Pan-Cancer analysis is freely available at http://starbase.sysu.edu.cn/panCancer.php

starBase provides the following Pan-Cancer Analysis Services:
1. starBase constructed Pan-Cancer expression profiles of lncRNAs, miRNAs from TCGA RNA-Seq and miRNA-Seq data.
2. starBase generated Pan-Cancer networks of CLIP-Seq experimentally supported miRNA-lncRNA and miRNA-mRNA interactions.
3. starBase identified Pan-Cancer ceRNA networks involving lncRNAs and mRNAs by analyzing >6000 tumor and normal samples and CLIP-Seq suppored miRNA-target interactions.
4. starBase firstly provided Pan-Cancer maps of interactions between RNA-binding proteins (RBPs) and RNAs(lncRNAs, mRNAs).
5. starBase provides interactive BarPlot, ScatterPlot and BoxPlot charts to show the above-mentioned genes and regulatory networks.

This platform will greatly help biologists to explore the impact of lncRNA, miRNA, mRNA, RNA-Binding Protein genes and their regulatory networks on human cancers and other diseases.

Pan-Cancer Analysis Platform

Identification of small ORFs in vertebrates using ribosome footprinting and evolutionary conservation

Posted by rnablog on April 17th, 2014

Identification of the coding elements in the genome is a fundamental step to understanding the building blocks of living systems. Short peptides (< 100 aa) have emerged as important regulators of development and physiology, but their identification has been limited by their size. We have leveraged the periodicity of ribosome movement on the mRNA to define actively translated ORFs by ribosome footprinting. This approach identifies several hundred translated small ORFs in zebrafish and human. Computational prediction of small ORFs from codon conservation patterns corroborates and extends these findings and identifies conserved sequences in zebrafish and human, suggesting functional peptide products (micropeptides). These results identify micropeptide-encoding genes in vertebrates, providing an entry point to define their function in vivo.

Identification of small ORFs in vertebrates using ribosome footprinting and evolutionary conservation.
Bazzini AA1, Johnstone TG, Christiano R, Mackowiak SD, Obermayer B, Fleming ES, Vejnar CE, Lee MT, Rajewsky N, Walther TC, Giraldez AJ.
EMBO J. 2014 Apr 4. [PMID:24705786]

A novel RNA motif mediates the strict nuclear localization of a long non-coding RNA

Posted by rnablog on April 17th, 2014

The ubiquitous presence of long non-coding RNAs (lncRNAs) in eukaryotes points to the importance of understanding how their sequences impact function. As many lncRNAs regulate nuclear events and thus must localize to nuclei, we analyzed the sequence requirements for nuclear localization in an intergenic lncRNA named BORG, which is both spliced and polyadenylated but strictly localized in nuclei. Subcellular localization of BORG was not dependent on the context or level of its expression or decay, but rather depended on the sequence of the mature, spliced transcript. Mutational analyses indicated that nuclear localization of BORG was mediated through a novel RNA motif consisting of the pentamer sequence AGCCC with sequence restrictions at positions -8 (T or A) and -3 (G or C) relative to the first nucleotide of the pentamer. Mutation of the motif to a scrambled sequence resulted in complete loss of nuclear localization, while addition of even a single copy of the motif to a cytoplasmically-localized RNA was sufficient to impart nuclear localization. Further, the presence of this motif in other cellular RNAs showed a direct correlation with nuclear localization, suggesting that this motif may act as a general nuclear localization signal for cellular RNAs.

A novel RNA motif mediates the strict nuclear localization of a long non-coding RNA.
Zhang B1, Gunawardane L, Niazi F, Jahanbani F, Chen X, Valadkhan S.
Mol Cell Biol. 2014 Apr 14. [PMID:24732794]

The lncRNAs PCGEM1 and PRNCR1 are not implicated in castration resistant prostate cancer

Posted by rnablog on April 17th, 2014

Long noncoding RNAs (lncRNAs) are increasingly implicated in cancer biology, contributing to essential cancer cell functions such as proliferation, invasion, and metastasis. In prostate cancer, several lncRNAs have been nominated as critical actors in disease pathogenesis. Among these, expression of PCGEM1 and PRNCR1 has been identified as a possible component in disease progression through the coordination of androgen receptor (AR) signaling (Yang et al., Nature 2013, see ref. [1]). However, concerns regarding the robustness of these findings have been suggested. Here, we sought to evaluate whether PCGEM1 and PRNCR1 are associated with prostate cancer. Through a comprehensive analysis of RNA-sequencing data (RNA-seq), we find evidence that PCGEM1 but not PRNCR1 is associated with prostate cancer. We employ a large cohort of >230 high-risk prostate cancer patients with long-term outcomes data to show that, in contrast to prior reports, neither gene is associated with poor patient outcomes. We further observe no evidence that PCGEM1 nor PRNCR1 interact with AR, and neither gene is a component of AR signaling. Thus, we conclusively demonstrate that PCGEM1 and PRNCR1 are not prognostic lncRNAs in prostate cancer and we refute suggestions that these lncRNAs interact in AR signaling.

The lncRNAs PCGEM1 and PRNCR1 are not implicated in castration resistant prostate cancer.
Prensner JR1, Sahu A, Iyer MK, Malik R, Chandler B, Asangani IA, Poliakov A, Vergara IA, Alshalalfa M, Jenkins RB, Davicioni E, Feng FY, Chinnaiyan AM.
Oncotarget. 2014 Mar 23. [PMID:24727738]

The human long noncoding RNA, lnc-IL7R, regulates inflammatory response

Posted by rnablog on April 17th, 2014

Long noncoding RNAs (lncRNAs), once thought to be transcriptional noise, have been recently shown to regulate a variety of biological processes. However, there is not much knowledge regarding their roles in inflammatory response. In this study, we performed human lncRNA microarray assays and identified a number of lncRNAs that demonstrated altered expression in response to LPS stimulation. Of these lncRNAs, lnc-IL7R, which overlaps with the 3′ untranslated region (3′ UTR) of the human interleukin-7 receptor α-subunit gene (IL7R) gene, was significantly upregulated in LPS treated cells. Functionally, lnc-IL7R was capable of diminishing LPS-induced inflammatory response, demonstrated by elevated expression of LPS induced E-selectin, VCAM-1, IL-6 and IL-8 in lnc-IL7R knockdown cells. Mechanistically, we found that lnc-IL7R knockdown diminished trimethylation of histone H3 at lysine 27 (H3K27me3), a hallmark of silent transcription, at the proximal promoters of inflammatory mediators. Our data suggest that lnc-IL7R contributes another layer of complexity in regulation of inflammatory response.

The human long noncoding RNA, lnc-IL7R, regulates inflammatory response.
Cui H1, Xie N, Tan Z, Banerjee S, Thannickal VJ, Abraham E, Liu G.
Eur J Immunol. 2014 Apr 11. [PMID:24723426]

Role of the lncRNA-p53 regulatory network in cancer

Posted by rnablog on April 17th, 2014

Advances in functional genomics have led to discovery of a large group of previous uncharacterized long non-coding RNAs (lncRNAs). Emerging evidence indicates that lncRNAs may serve as master gene regulators through various mechanisms. Dysregulation of lncRNAs is often associated with a variety of human diseases including cancer. Of significant interest, recent studies suggest that lncRNAs participate in the p53 tumor suppressor regulatory network. In this review, we discuss how lncRNAs serve as p53 regulators or p53 effectors. Further characterization of these p53-associated lncRNAs in cancer will provide a better understanding of lncRNA-mediated gene regulation in the p53 pathway. As a result, lncRNAs may prove to be valuable biomarkers for cancer diagnosis or potential targets for cancer therapy.

Role of the lncRNA-p53 regulatory network in cancer.
Zhang A1, Xu M, Mo YY.
J Mol Cell Biol. 2014 Apr 9. [PMID:24721780]

Long non-coding RNAs: A novel endogenous source for the generation of Dicer-like 1-dependent small RNAs in Arabidopsis thaliana

Posted by rnablog on April 17th, 2014

The biological relevance of long non-coding RNAs (lncRNAs) is emerging. Whether the lncRNAs could form structured precursors for small RNAs (sRNAs) production remains elusive. Here, 172 713 DCL1 (Dicer-like 1)-dependent sRNAs were identified in Arabidopsis. Except for the sRNAs mapped onto the microRNA precursors, the remaining ones led us to investigate their originations. Intriguingly, 65 006 sRNAs found their loci on 5891 lncRNAs. These sRNAs were sent to AGO (Argonaute) enrichment analysis. As a result, 1264 sRNAs were enriched in AGO1, which were then subjected to target prediction. Based on degradome sequencing data, 109 transcripts were validated to be targeted by 96 sRNAs. Besides, 44 lncRNAs were targeted by 23 sRNAs. To further support the origination of the DCL1-dependent sRNAs from lncRNAs, we searched for the degradome-based cleavage signals at either ends of the sRNA loci, which were supposed to be produced during DCL1-mediated processing of the long-stem structures. As a result, 63 612 loci were supported by degradome signatures. Among these loci, 6606 reside within the dsRNA-seq (double-stranded RNA sequencing) read-covered regions of 100 nt or longer. These regions were subjected to secondary structure prediction. And, 43 regions were identified to be capable of forming highly complementary long-stem structures. We proposed that these local long-stem structures could be recognized by DCL1 for cropping, thus serving as the sRNA precursors. We hope that our study could inspire more research efforts to study on the biological roles of the lncRNAs in plants.

Long non-coding RNAs: A novel endogenous source for the generation of Dicer-like 1-dependent small RNAs in Arabidopsis thaliana.
Ma X1, Shao C2, Jin Y3, Wang H1, Meng Y1.
RNA Biol. 2014 Apr 4;11(4). [PMID:24717238]

CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation

Posted by rnablog on April 10th, 2014

Abnormal mitochondrial fission participates in the pathogenesis of many diseases. Long non-coding RNAs (lncRNAs) are emerging as new players in gene regulation, but how lncRNAs operate in the regulation of mitochondrial network is unclear. Here we report that a lncRNA, named cardiac apoptosis-related lncRNA (CARL), can suppress mitochondrial fission and apoptosis by targeting miR-539 and PHB2. The results show that PHB2 is able to inhibit mitochondrial fission and apoptosis. miR-539 is responsible for the dysfunction of PHB2 and regulates mitochondrial fission and apoptosis by targeting PHB2. Further, we show that CARL can act as an endogenous miR-539 sponge that regulates PHB2 expression, mitochondrial fission and apoptosis. Our present study reveals a model of mitochondrial fission regulation that is composed of CARL, miR-539 and PHB2. Modulation of their levels may provide a new approach for tackling apoptosis and myocardial infarction.

CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation.
Wang K1, Long B1, Zhou LY1, Liu F1, Zhou QY2, Liu CY1, Fan YY1, Li PF1.
Nat Commun. 2014 Apr 7;5:3596. [PMID:24710105]

Analysing the relationship between lncRNA and protein-coding gene and the role of lncRNA as ceRNA in pulmonary fibrosis

Posted by rnablog on April 10th, 2014

Long non-coding RNAs (lncRNAs) are involved in various pathophysiologic processes and human diseases. However, their dynamics and corresponding functions in pulmonary fibrosis remain poorly understood. In this study, portions of lncRNAs adjacent or homologous to protein-coding genes were determined by searching the UCSC genome bioinformatics database. This was found to be potentially useful for exploring lncRNA functions in disease progression. Previous studies showed that competing endogenous RNA (ceRNA) hypothesis is another method to predict lncRNA function. However, little is known about the function of ceRNA in pulmonary fibrosis. In this study, we selected two differentially expressed lncRNAs MRAK088388 and MRAK081523 to explore their regulatory mechanisms. MRAK088388 and MRAK081523 were analysed as long-intergenic non-coding RNAs (lincRNAs), and identified as orthologues of mouse lncRNAs AK088388 and AK081523, respectively. qRT-PCR and in situ hybridization (ISH) showed that they were significantly up-regulated, and located in the cytoplasm of interstitial lung cells. We also showed that MRAK088388 and N4bp2 had the same miRNA response elements (MREs) for miR-200, miR-429, miR-29, and miR-30, whereas MRAK081523 and Plxna4 had the same MREs for miR-218, miR-141, miR-98, and let-7. Moreover, the expression levels of N4bp2 and Plxna4 significantly increased in fibrotic rats, and were highly correlated with those of MRAK088388 and MRAK081523, respectively. Among their shared miRNAs, miR-29b-3p and let-7i-5p decreased in the model group, and were negatively correlated with the expression of MRAK088388 and MRAK081523, respectively. MRAK088388 and MRAK081523 could regulate N4bp2 and Plxna4 expression by sponging miR-29b-3p and let-7i-5p, respectively, and possessed regulatory functions as ceRNAs. Thus, our study may provide insights into the functional interactions of lncRNA, miRNA and mRNA, and lead to new theories for the pathogenesis and treatment of pulmonary fibrosis.

Analysing the relationship between lncRNA and protein-coding gene and the role of lncRNA as ceRNA in pulmonary fibrosis.
Song X1, Cao G, Jing L, Lin S, Wang X, Zhang J, Wang M, Liu W, Lv C.
J Cell Mol Med. 2014 Apr 6. [PMID:24702795]

The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity

Posted by rnablog on April 10th, 2014

Human endogenous retrovirus subfamily H (HERVH) is a class of transposable elements expressed preferentially in human embryonic stem cells (hESCs). Here, we report that the long terminal repeats of HERVH function as enhancers and that HERVH is a nuclear long noncoding RNA required to maintain hESC identity. Furthermore, HERVH is associated with OCT4, coactivators and Mediator subunits. Together, these results uncover a new role of species-specific transposable elements in hESCs.

The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity.
Lu X1, Sachs F2, Ramsay L3, Jacques PÉ4, Göke J1, Bourque G5, Ng HH6.
Nat Struct Mol Biol. 2014 Apr;21(4):423-5. [PMID:24681886]

The Noncoding RNA Revolution-Trashing Old Rules to Forge New Ones

Posted by rnablog on April 10th, 2014

Noncoding RNAs (ncRNAs) accomplish a remarkable variety of biological functions. They regulate gene expression at the levels of transcription, RNA processing, and translation. They protect genomes from foreign nucleic acids. They can guide DNA synthesis or genome rearrangement. For ribozymes and riboswitches, the RNA structure itself provides the biological function, but most ncRNAs operate as RNA-protein complexes, including ribosomes, snRNPs, snoRNPs, telomerase, microRNAs, and long ncRNAs. Many, though not all, ncRNAs exploit the power of base pairing to selectively bind and act on other nucleic acids. Here, we describe the pathway of ncRNA research, where every established “rule” seems destined to be overturned.

The Noncoding RNA Revolution-Trashing Old Rules to Forge New Ones.
Cech TR1, Steitz JA2.
Cell. 2014 Mar 27;157(1):77-94. [PMID:24679528]


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