Cited by 4,098Cancer-related molecular mechanisms researchGenomics and Chromatin DynamicsChromosomal and Genetic Variations

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

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Guttman, Mitchell, Amit, Ido, Garber, Manuel, French, Courtney, Lin, Michael F., Feldser, David, Huarte, Maite, Zuk, Or, Carey, Bryce W., Cassady, John P., Cabili, Moran N., Jaenisch, Rudolf, Mikkelsen, Tarjei S., Jacks, Tyler, Hacohen, Nir, Bernstein, Bradley E., Kellis, Manolis, Regev, Aviv, Rinn, John L., Lander, Eric S.·2009·Nature

DOI 10.1038/nature07672PMC PMC2754849

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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 approximately 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, NFkappaB, 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.

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Authors: Guttman, M., Amit, I., Garber, M., French, C., Lin, M. F., Feldser, D., Huarte, M., Zuk, O., Carey, B. W., Cassady, J. P., Cabili, M. N., Jaenisch, R., Mikkelsen, T. S., Jacks, T., Hacohen, N., Bernstein, B. E., Kellis, M., Regev, A., Rinn, J. L., & Lander, E. S.
Affiliations: Broad Institute (US)
Koch Institute for Integrative Cancer Research At MIT (US)
Whitehead Institute for Biomedical Research (US)
Harvard University (US)
Corresponding author: Rinn, John L.
ORCID: Guttman, Mitchell
Amit, Ido
Garber, Manuel
French, Courtney
Lin, Michael F.
Feldser, David
Huarte, Maite
Zuk, Or
Cabili, Moran N.
Jaenisch, Rudolf
Mikkelsen, Tarjei S.
Jacks, Tyler
Hacohen, Nir
Bernstein, Bradley E.
Kellis, Manolis
Regev, Aviv
Rinn, John L.
Lander, Eric S.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2009-02-01
Volume: 458
Issue: 7235
Pages: 223-227
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature07672
PMC: PMC2754849
OpenAlex: W1999746344
Cited by: 4,098
References: 39
Citations by year: 2026: 34 · 2025: 85 · 2024: 128 · 2023: 168 · 2022: 233 · 2021: 331 · 2020: 274 · 2019: 301 · 2018: 331 · 2017: 330 · 2016: 322 · 2015: 334 · 2014: 315 · 2013: 266 · 2012: 249
FWCI: 72.16
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
CaltechAUTHORS (California Institute of Technology) (submittedVersion)
RePEc: Research Papers in Economics (submittedVersion)
DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion)
Funders: National Institutes of Health (DP1OD003958)
National Human Genome Research Institute (U54HG003067, R01HG004037)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
Keywords: long intergenic non-coding RNA, chromatin state, evolutionary conservation, purifying selection, embryonic stem cell pluripotency, cell proliferation, transcription factor regulation, p53, NF-κB, SOX2, Oct4, Nanog, transcriptional noise
MeSH terms: Animals, Base Sequence, Cells, Cultured, Chromatin, Exons, Mammals, Promoter Regions, Genetic, RNA, Transcription Factors, Reproducibility of Results, Conserved Sequence, DNA, Intergenic, Mice

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

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