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Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals
Open accessAbstract
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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“LincRNAs were collected from reconstructed transcripts (Guttman et al., 2010) that lay entirely within the lincRNA chromatin signatures identified by Guttman et al. (Guttman et al., 2009), which excluded known protein-coding genes.”
From Ribosome Profiling of Mouse Embryonic Stem Cells Reveals the Complexity and Dynamics of Mammalian Proteomes (2011) · cites this paper as Guttman et al., 2009
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“The following ncRNA databases are included in our analysis: miRBase version 22.1 (16), Ensembl ncRNA version 100 (44), RNACentral version 15 (45), GtRNAdb version 18.1 (17) and NONCODE version 5 (46).”
From miRNATissueAtlas2: an update to the human miRNA tissue atlas (2022) · cites this paper as [44]
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“(1) Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge MA 02142 (2) Department of Biology, Massachusetts Institute of Technology, Cambridge MA 02139 (3) Department of Pathology, Beth Israel Deaconess Medical Center, Boston MA 02215 (4) Division of Health Sciences and Technology, Massachusetts Institute…”
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Metadata
- 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
- Venue
- Nature
- Published
- 2009-02-01
- Volume
- 458
- Issue
- 7235
- Pages
- 223-227
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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