Evidence for Transcript Networks Composed of Chimeric RNAs in Human Cells

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. This work has been supported by grants U01HG003150 and U01HG003147 from the National Human Genome Research for the ENCODE project. RG was also supported by a grant from the Spanish Ministry of Education and Science. In addition, KS-A, RM, XY, CL, LG and MV were supported by a grant from the Ellison Foundation and as Institute Sponsored Research from the Dana Farber Cancer Institute Strategic Initiative. The laboratories of SA and AR were supported by grants from the Swiss National Science Foundation and the European Commission AnEUploidy Integrated Project. SA was also supported by the National Center of Excellence ‘‘Frontiers in Genetics’’, ChildCare Foundation and an ERC grant from the European Union. AF, TH and JM acknowledge support from the Wellcome Trust. The work of JLG and MO has been supported by the Spanish Ministry of Science (CTQ2005-09365-C02-02, BIO2009-10964), Instituto Nacional de Bioinformática, the Consolider E-science project (CSD2007-00050), COMBIOMED RETICS and the Fundación Marcelino Botin. JD is supported by a grant from the National Institutes of Health (HG003143) and a W. M. Keck Foundation Distinguished Young Scholar Award. JS is supported by a grant from the National Institutes of Health (U54 HG004592). The work of MT and AV was supported by Consolider E-Science (CSD2007-00050) and the Instituto Nacional de Bioinformática. MV (Center for Cancer Systems Biology, CCSB) is a ‘‘Chercheur Qualifié Honoraire’’ from the Fonds de la Recherche Scientifique (FRS-FNRS, French Community of Belgium). This work has also been funded by grant to TG by NHGRI (U54HG004557) and partially byAffymetirix, Corp