Chromatin Signature Reveals over a Thousand Highly Conserved Large Non-Coding Rnas in Mammals
There is growing recognition that mammalian cells produce many thousands of large intergenic transcripts [1, 2, 3, 4]. However, the functional significance of these transcripts has been particularly controversial. Although there are some well-characterized examples, most (>95%) show little eviden...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Nature Publishing Group
2010
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| Online Access: | http://hdl.handle.net/1721.1/58204 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0001-8567-2049 |
| _version_ | 1826213952030244864 |
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| author | Guttman, Mitchell Amit, Ido Garber, Manuel French, Courtney Lin, Michael F. Feldser, David M. Huarte, Maite Zuk, Or Carey, Bryce W. Cassady, John P. Cabili, Moran N. Jaenisch, Rudolf Jacks, Tyler E. Hacohen, Nir Bernstein, Bradley E. Kellis, Manolis Lander, Eric S. Mikkelsen, Tarjei Sigurd, 1978- |
| author2 | Broad Institute of MIT and Harvard |
| author_facet | Broad Institute of MIT and Harvard Guttman, Mitchell Amit, Ido Garber, Manuel French, Courtney Lin, Michael F. Feldser, David M. Huarte, Maite Zuk, Or Carey, Bryce W. Cassady, John P. Cabili, Moran N. Jaenisch, Rudolf Jacks, Tyler E. Hacohen, Nir Bernstein, Bradley E. Kellis, Manolis Lander, Eric S. Mikkelsen, Tarjei Sigurd, 1978- |
| author_sort | Guttman, Mitchell |
| collection | MIT |
| description | There is growing recognition that mammalian cells produce many thousands of large intergenic transcripts [1, 2, 3, 4]. 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 [5, 6]. 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. |
| first_indexed | 2024-09-23T15:57:27Z |
| format | Article |
| id | mit-1721.1/58204 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:57:27Z |
| publishDate | 2010 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/582042022-09-29T17:18:26Z Chromatin Signature Reveals over a Thousand Highly Conserved Large Non-Coding Rnas in Mammals Guttman, Mitchell Amit, Ido Garber, Manuel French, Courtney Lin, Michael F. Feldser, David M. Huarte, Maite Zuk, Or Carey, Bryce W. Cassady, John P. Cabili, Moran N. Jaenisch, Rudolf Jacks, Tyler E. Hacohen, Nir Bernstein, Bradley E. Kellis, Manolis Lander, Eric S. Mikkelsen, Tarjei Sigurd, 1978- Broad Institute of MIT and Harvard Harvard University--MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Koch Institute for Integrative Cancer Research at MIT Regev, Aviv Regev, Aviv Guttman, Mitchell Amit, Ido Garber, Manuel French, Courtney Lin, Michael F. Feldser, David M. Huarte, Maite Zuk, Or Carey, Bryce W. Cassady, John P. Jaenisch, Rudolf Mikkelsen, Tarjei Sigurd Jacks, Tyler E. Hacohen, Nir Kellis, Manolis Lander, Eric S. There is growing recognition that mammalian cells produce many thousands of large intergenic transcripts [1, 2, 3, 4]. 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 [5, 6]. 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. Beth Israel Deaconess Medical Center National Human Genome Research Institute (U.S.) Broad Institute 2010-09-02T15:08:39Z 2010-09-02T15:08:39Z 2009-02 2008-08 Article http://purl.org/eprint/type/SubmittedJournalArticle 0028-0836 1476-4687 http://hdl.handle.net/1721.1/58204 Guttman, Mitchell et al. “Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals.” Nature 458.7235 (2009): 223-227. https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0001-8567-2049 en_US http://dx.doi.org/10.1038/nature07672 Nature Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Nature Publishing Group Aviv Regev |
| spellingShingle | Guttman, Mitchell Amit, Ido Garber, Manuel French, Courtney Lin, Michael F. Feldser, David M. Huarte, Maite Zuk, Or Carey, Bryce W. Cassady, John P. Cabili, Moran N. Jaenisch, Rudolf Jacks, Tyler E. Hacohen, Nir Bernstein, Bradley E. Kellis, Manolis Lander, Eric S. Mikkelsen, Tarjei Sigurd, 1978- Chromatin Signature Reveals over a Thousand Highly Conserved Large Non-Coding Rnas in Mammals |
| title | Chromatin Signature Reveals over a Thousand Highly Conserved Large Non-Coding Rnas in Mammals |
| title_full | Chromatin Signature Reveals over a Thousand Highly Conserved Large Non-Coding Rnas in Mammals |
| title_fullStr | Chromatin Signature Reveals over a Thousand Highly Conserved Large Non-Coding Rnas in Mammals |
| title_full_unstemmed | Chromatin Signature Reveals over a Thousand Highly Conserved Large Non-Coding Rnas in Mammals |
| title_short | Chromatin Signature Reveals over a Thousand Highly Conserved Large Non-Coding Rnas in Mammals |
| title_sort | chromatin signature reveals over a thousand highly conserved large non coding rnas in mammals |
| url | http://hdl.handle.net/1721.1/58204 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0001-8567-2049 |
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