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Evidence for transcript networks composed of chimeric RNAs in human cells.

ABSTRACT: The classic organization of a gene structure has followed the Jacob and Monod bacterial gene model proposed more than 50 years ago. Since then, empirical determinations of the complexity of the transcriptomes found in yeast to human has blurred the definition and physical boundaries of genes. Using multiple analysis approaches we have characterized individual gene boundaries mapping on human chromosomes 21 and 22. Analyses of the locations of the 5' and 3' transcriptional termini of 492 protein coding genes revealed that for 85% of these genes the boundaries extend beyond the current annotated termini, most often connecting with exons of transcripts from other well annotated genes. The biological and evolutionary importance of these chimeric transcripts is underscored by (1) the non-random interconnections of genes involved, (2) the greater phylogenetic depth of the genes involved in many chimeric interactions, (3) the coordination of the expression of connected genes and (4) the close in vivo and three dimensional proximity of the genomic regions being transcribed and contributing to parts of the chimeric RNAs. The non-random nature of the connection of the genes involved suggest that chimeric transcripts should not be studied in isolation, but together, as an RNA network.

SUBMITTER: Djebali S

PROVIDER: S-EPMC3251577 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Evidence for transcript networks composed of chimeric RNAs in human cells.

Djebali Sarah S Lagarde Julien J Kapranov Philipp P Lacroix Vincent V Borel Christelle C Mudge Jonathan M JM Howald Cédric C Foissac Sylvain S Ucla Catherine C Chrast Jacqueline J Ribeca Paolo P Martin David D Murray Ryan R RR Yang Xinping X Ghamsari Lila L Lin Chenwei C Bell Ian I Dumais Erica E Drenkow Jorg J Tress Michael L ML Gelpí Josep Lluís JL Orozco Modesto M Valencia Alfonso A van Berkum Nynke L NL Lajoie Bryan R BR Vidal Marc M Stamatoyannopoulos John J Batut Philippe P Dobin Alex A Harrow Jennifer J Hubbard Tim T Dekker Job J Frankish Adam A Salehi-Ashtiani Kourosh K Reymond Alexandre A Antonarakis Stylianos E SE Guigó Roderic R Gingeras Thomas R TR

PloS one 20120104 1

The classic organization of a gene structure has followed the Jacob and Monod bacterial gene model proposed more than 50 years ago. Since then, empirical determinations of the complexity of the transcriptomes found in yeast to human has blurred the definition and physical boundaries of genes. Using multiple analysis approaches we have characterized individual gene boundaries mapping on human chromosomes 21 and 22. Analyses of the locations of the 5' and 3' transcriptional termini of 492 protein ...[more]

PMID: 22238572

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Project description:BackgroundHepatic fibrosis is the underlying cause of cirrhosis and liver failure in nearly every form of chronic liver disease, and hepatic stellate cells (HSCs) are the primary cell type responsible for fibrosis. Long noncoding RNAs (lncRNAs) are increasingly recognized as regulators of development and disease; however, little is known about their expression in human HSCs and their function in hepatic fibrosis.MethodsWe performed RNA sequencing and ab initio assembly of RNA transcripts to define the lncRNAs expressed in human HSC myofibroblasts. We analyzed chromatin immunoprecipitation data and expression data to identify lncRNAs that were regulated by transforming growth factor beta (TGF-β) signaling, associated with super-enhancers and restricted in expression to HSCs compared with 43 human tissues and cell types. Co-expression network analyses were performed to discover functional modules of lncRNAs, and principle component analysis and K-mean clustering were used to compare lncRNA expression in HSCs with other myofibroblast cell types.ResultsWe identified over 3600 lncRNAs that are expressed in human HSC myofibroblasts. Many are regulated by TGF-β, a major fibrotic signal, and form networks with genes encoding key components of the extracellular matrix (ECM), which is the substrate of the fibrotic scar. The lncRNAs directly regulated by TGF-β signaling are also enriched at super-enhancers. More than 400 of the lncRNAs identified in HSCs are uniquely expressed in HSCs compared with 43 other human tissues and cell types and HSC myofibroblasts demonstrate different patterns of lncRNA expression compared with myofibroblasts originating from other tissues. Co-expression analyses identified a subset of lncRNAs that are tightly linked to collagen genes and numerous proteins that regulate the ECM during formation of the fibrotic scar. Finally, we identified lncRNAs that are induced during progression of human liver disease.ConclusionslncRNAs are likely key contributors to the formation and progression of fibrosis in human liver disease.

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Evidence for transcript networks composed of chimeric RNAs in human cells.

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Evidence for transcript networks composed of chimeric RNAs in human cells.

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