The majority of total nuclear-encoded non-ribosomal RNA in a human cell is 'dark matter' un-annotated RNA

Philipp Kapranov*, Georges St Laurent, Tal Raz, Fatih Ozsolak, C. Patrick Reynolds, Poul H.B. Sorensen, Gregory Reaman, Patrice Milos, Robert J. Arceci, John F. Thompson, Timothy J. Triche

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

231 Scopus citations

Abstract

Background: Discovery that the transcriptional output of the human genome is far more complex than predicted by the current set of protein-coding annotations and that most RNAs produced do not appear to encode proteins has transformed our understanding of genome complexity and suggests new paradigms of genome regulation. However, the fraction of all cellular RNA whose function we do not understand and the fraction of the genome that is utilized to produce that RNA remain controversial. This is not simply a bookkeeping issue because the degree to which this un-annotated transcription is present has important implications with respect to its biologic function and to the general architecture of genome regulation. For example, efforts to elucidate how non-coding RNAs (ncRNAs) regulate genome function will be compromised if that class of RNAs is dismissed as simply 'transcriptional noise'.Results: We show that the relative mass of RNA whose function and/or structure we do not understand (the so called 'dark matter' RNAs), as a proportion of all non-ribosomal, non-mitochondrial human RNA (mt-RNA), can be greater than that of protein-encoding transcripts. This observation is obscured in studies that focus only on polyA-selected RNA, a method that enriches for protein coding RNAs and at the same time discards the vast majority of RNA prior to analysis. We further show the presence of a large number of very long, abundantly-transcribed regions (100's of kb) in intergenic space and further show that expression of these regions is associated with neoplastic transformation. These overlap some regions found previously in normal human embryonic tissues and raises an interesting hypothesis as to the function of these ncRNAs in both early development and neoplastic transformation.Conclusions: We conclude that 'dark matter' RNA can constitute the majority of non-ribosomal, non-mitochondrial-RNA and a significant fraction arises from numerous very long, intergenic transcribed regions that could be involved in neoplastic transformation.

Original languageAmerican English
Article number149
JournalBMC Biology
Volume8
DOIs
StatePublished - 21 Dec 2010
Externally publishedYes

Bibliographical note

Funding Information:
TJT wishes to acknowledge and thank Dr Jim Jacobson, Acting Associate Director and Chief, Diagnostic Biomarker and Technologies Branch, Cancer Diagnosis Program, DCTD NCI (deceased) for his continuous support of the work that led to this study as an outgrowth of NCI funded UO1 studies (Director’s Challenge and SPECS). We thank Dr Jason Farrar for his careful reading of the manuscript; Drs Sylvain Foissac, Doron Lipson and Stan Letovsky for their helpful discussions; Drs Michele Wing and Yuxia Zhan in the Genome Core at CHLA for their help with the RNA preparation; Dr Hiro Shimada for help with the EFT tissue handling; and members of the Triche laboratory for their help. The work was supported by a grant from the Department of Defense (CDMRP), W81XWH-07-1-0580 and through support of the Children’s Oncology Group (COG) Chair’s grant, U-10 CA98543 from the NIH; by Rett’s Initiative and by the UO1 SPECS program (Dr Triche PI). RJA is partially supported through the endowed King Fahd Professorship in Pediatric Oncology at Johns Hopkins. This publication was made possible in part by grant RC2 HG005598 (JFT) from the National Human Genetics Research Institute (NHGRI) at the National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NHGRI.

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