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Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals

Guttman, Mitchell and Amit, Ido and Garber, Manuel and French, Courtney and Lin, Michael F. and Feldser, David and Huarte, Maite and Zuk, Or and Carey, Bryce W. and Cassady, John P. and Cabili, Moran N. and Jaenisch, Rudolf and Mikkelsen, Tarjei S. and Jacks, Tyler and Hacohen, Nir and Bernstein, Bradley E. and Kellis, Manolis and Regev, Aviv and Rinn, John L. and Lander, Eric S. (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature, 458 (7235). pp. 223-227. ISSN 0028-0836. PMCID PMC2754849. https://resolver.caltech.edu/CaltechAUTHORS:20161121-144950442

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Abstract

There is growing recognition that mammalian cells produce many thousands of large intergenic transcripts. However, the functional significance of these transcripts has been particularly controversial. Although there are some well-characterized examples, most (>95%) show little evidence of evolutionary conservation and have been suggested to represent transcriptional noise. Here we report a new approach to identifying large non-coding RNAs using chromatin-state maps to discover discrete transcriptional units intervening known protein-coding loci. Our approach identified ~1,600 large multi-exonic RNAs across four mouse cell types. In sharp contrast to previous collections, these large intervening non-coding RNAs (lincRNAs) show strong purifying selection in their genomic loci, exonic sequences and promoter regions, with greater than 95% showing clear evolutionary conservation. We also developed a functional genomics approach that assigns putative functions to each lincRNA, demonstrating a diverse range of roles for lincRNAs in processes from embryonic stem cell pluripotency to cell proliferation. We obtained independent functional validation for the predictions for over 100 lincRNAs, using cell-based assays. In particular, we demonstrate that specific lincRNAs are transcriptionally regulated by key transcription factors in these processes such as p53, NFκB, Sox2, Oct4 (also known as Pou5f1) and Nanog. Together, these results define a unique collection of functional lincRNAs that are highly conserved and implicated in diverse biological processes.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1038/nature07672DOIArticle
http://www.nature.com/nature/journal/v458/n7235/full/nature07672.htmlPublisherArticle
http://www.nature.com/nature/journal/v458/n7235/suppinfo/nature07672.htmlPublisherSupplementary Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754849/PubMed CentralArticle
http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE13765OrganizationGene Expression Omnibus
http://rdcu.be/mQkyPublisherFree ReadCube access
ORCID:
AuthorORCID
Guttman, Mitchell0000-0003-4748-9352
Regev, Aviv0000-0003-3293-3158
Lander, Eric S.0000-0003-2662-4631
Additional Information:© 2009 Macmillan Publishers Limited. Received 5 August 2008; Accepted 25 November 2008; Published online 1 February 2009. We would like to thank our colleagues at the Broad Institute, especially J. P. Mesirov for discussions and statistical insights, X. Xie for statistical help with conservation analyses, J. Robinson for visualization help, M. Ku, E. Mendenhall and X. Zhang for help generating ChIP samples, and N. Novershtern and A. Levy for providing transcription factor lists. M. Guttman is a Vertex scholar, I.A. acknowledges the support of the Human Frontier Science Program Organization. This work was funded by Beth Israel Deaconess Medical Center, National Human Genome Research Institute, and the Broad Institute of MIT and Harvard. Author Contributions: J.L.R., E.S.L., A.R. and M. Guttman conceived and designed experiments. The manuscript was written by M. Guttman, A.R., J.L.R. and E.S.L. J.L.R., I.A., C.F., D.F., M.H., B.W.C., J.P.C. and M. Guttman performed molecular biology experiments. All data analyses were performed by M. Guttman in conjunction with M. Garber (conservation analyses), M.F.L. (codon substitution frequency), T.S.M. (ChlP-seq data), O.Z. (motif analysis) and M.N.C. (lincRNA genomic location analysis). Reagents were provided by M. Garber (pre-published conservation analysis tools); T.J. and D.F. (p53 wild-type and knockout MEFs); N.H., A.R. and I.A. (dendritic cell stimulated time course); B.E.B. (ChlP data); R.J., B.W.C. and J.P.C. (luciferase assays); and M.K. and M.F.L. (codon substitution frequency code). Microarray data have been deposited in the Gene Expression Omnibus (GEO) under accession number GSE13765.
Funders:
Funding AgencyGrant Number
Vertex ScholarshipUNSPECIFIED
Human Frontier Science ProgramUNSPECIFIED
Beth Israel Deaconess Medical CenterUNSPECIFIED
National Human Genome Research InstituteUNSPECIFIED
Broad Institute of MIT and HarvardUNSPECIFIED
NIHUNSPECIFIED
Issue or Number:7235
PubMed Central ID:PMC2754849
Record Number:CaltechAUTHORS:20161121-144950442
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20161121-144950442
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:72212
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Nov 2016 23:10
Last Modified:09 Mar 2020 13:19

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