Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals (original) (raw)

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Microarray data have been deposited in the Gene Expression Omnibus (GEO) under accession number GSE13765.

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Acknowledgements

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).

Author information

Author notes

1. John L. Rinn and Eric S. Lander: These authors contributed equally to this work.

Authors and Affiliations

1. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA,
   Mitchell Guttman, Ido Amit, Manuel Garber, Courtney French, Michael F. Lin, Maite Huarte, Or Zuk, Tarjei S. Mikkelsen, Nir Hacohen, Bradley E. Bernstein, Manolis Kellis, Aviv Regev, John L. Rinn & Eric S. Lander
2. Department of Biology,,
   Mitchell Guttman, Bryce W. Carey, John P. Cassady, Rudolf Jaenisch, Tyler Jacks, Aviv Regev & Eric S. Lander
3. The Koch Institute for Integrative Cancer Research,,
   David Feldser & Tyler Jacks
4. Division of Health Sciences and Technology, and,
   Tarjei S. Mikkelsen
5. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,
   Manolis Kellis
6. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA,
   Maite Huarte & John L. Rinn
7. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02114, USA,
   Moran N. Cabili & Eric S. Lander
8. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA,
   Bryce W. Carey, John P. Cassady, Rudolf Jaenisch & Eric S. Lander
9. Center for Immunology and Inflammatory Diseases,,
   Nir Hacohen
10. Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA,
    Bradley E. Bernstein
11. Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA,
    Bradley E. Bernstein & John L. Rinn

Authors

1. Mitchell Guttman
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2. Ido Amit
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3. Manuel Garber
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4. Courtney French
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5. Michael F. Lin
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6. David Feldser
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7. Maite Huarte
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8. Or Zuk
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9. Bryce W. Carey
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10. John P. Cassady
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11. Moran N. Cabili
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12. Rudolf Jaenisch
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13. Tarjei S. Mikkelsen
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14. Tyler Jacks
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15. Nir Hacohen
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16. Bradley E. Bernstein
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17. Manolis Kellis
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18. Aviv Regev
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19. John L. Rinn
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20. Eric S. Lander
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Corresponding author

Correspondence toJohn L. Rinn.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-11 with Legends (PDF 2081 kb)

Supplementary Information

This file contains Supplementary Methods and Supplementary References (PDF 147 kb)

Supplementary Table 1

In Supplementary Table 1 the K4-K36 domain coordinates are shown and the K4-K36 enriched domains in the 4 mouse cell types are listed. Coordinates are indicated in mouse genome build MM8. (XLS 107 kb)

Supplementary Table 2

In Supplementary Table 2 the lincRNA Exon Coordinates and Pi LOD Enrichment Score are shown. lincRNA exons defined by Nimbelegen tiling micorarrays are listed in mouse genome build MM9. Each exon has an associated Pi LOD Enrichment Score (Methods) reported. (XLS 174 kb)

Supplementary Table 3

In Supplementary Table 3 the characteristic properties of lincRNAs are shown. (DOC 36 kb)

Supplementary Table 4

In Supplementary Table 4 the PCR validation primer sequences are shown. Primer sequences used for validation of lincRNA expression by PCR and qPCR are reported. (XLS 31 kb)

Supplementary Table 5

In Supplementary Table 5 the Northern blot analysis probe sequences and primers are shown. Primers and amplicons for Northern blot analyses are provided. The correct file for Supplementary Table 5 was uploaded on 4th March, 2009. (XLS 27 kb)

Supplementary Table 6

In Supplementary Table 6 the Codon Substitution Frequency (CSF) Scores are shown. The CSF score for each K4-K36 domain is provided. Coordinates are reported in mouse genome build MM9. An updated version for Suplementary Table 6 was uploaded on 4th March, 2009 (XLS 122 kb)

Supplementary Table 7

In Supplementary Table 7 the Exon conservation for lincRNAs and other annotations are shown. Pi LOD Enrichment scores are provided for lincRNA exons and other annotations compared in the text. The coordinates are provided in Mouse genome MM9 and the max 12-mer LOD score as well as the randomized average max 12-mer LOD score is indicated along with the enrichment score. (XLS 836 kb)

Supplementary Table 8

In Supplementary Table 8 the lincRNA Promoter Conservation is shown. Pi LOD Enrichment scores are provided for each lincRNA promoter region, protein coding gene promoters, and random intergenic regions. Coordinates are provided in Mouse genome build MM9. (XLS 634 kb)

Supplementary Table 9

In Supplementary Table 9 the Human and Mouse orthologous lincRNAs are shown. lincRNAs defined in Human Lung Fibroblasts were lifted into the mouse genome (MM8) and enrichment statistics were computed for Mouse Lung Fibroblasts (Methods). The enrichment p-values and fold are indicated. (XLS 28 kb)

Supplementary Table 10

In Supplementary Table 10 the lincRNA expression across mouse tissue compendium is shown. lincRNA expression levels across various mouse cell types, tissues, and conditions are provided. The values are log values of the relative expression of each lincRNA. (XLS 420 kb)

Supplementary Table 11

In Supplementary Table 11 the Gene Set Enrichment Analysis (GSEA) association matrix is shown. Functional associations between lincRNAs (columns) and MSigDB terms (rows) are indicated. Positive association is indicated by a 1, negative association is indicated by an -1, and no association is indicated by a 0. (TXT 6203 kb)

Supplementary Table 12

In Supplementary Table 12 the P53 regulated lincRNAs upon DNA Damage Induction are shown. lincRNAs that temporally increase inP53 wild-type cells compared with P53 Knock-out cells upon stimulation with DNA damage are indicated along with their expression levels across the DNA damage time course. (XLS 26 kb)

Supplementary Table 13

In Supplementary Table 13 the P53 Motif Enrichments in induced lincRNAs are shown. P53 motif scores are provided for each lincRNA promoter along with the sequence of the best motif hit and its conservation. P53 induced lincRNAs are indicated in the last column. (XLS 347 kb)

Supplementary Table 14

In Supplementary Table 14 the NFKB regulated lincRNAs are shown. lincRNAs that are differentially expressed in TLR4 stimulation of BMDC cells compared with unstimulated BMDC cells are provided. (XLS 23 kb)

Supplementary Table 15

In Supplementary Table 15 the ES cells lincRNAs bound by Oct4 and/or Nanog are shown: The coordinates of the lincRNAs bound by Oct4/Nanog in ES cells is provided. (XLS 17 kb)

Supplementary Table 16

In Supplementary Table 16 the functional association of lincENC1 is shown. GSEA results for lincENC1 is provided for both profiled exons in the transcript. (XLS 23 kb)

Supplementary Table 17

In Supplementary Table 17the Enrichment of Gene Ontology (GO) terms for lincRNA neighbors is shown. Significant GO terms (FDR<.05) are indicated along with their associated p-values. (XLS 22 kb)

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Guttman, M., Amit, I., Garber, M. et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals.Nature 458, 223–227 (2009). https://doi.org/10.1038/nature07672

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• Received: 05 August 2008
• Accepted: 25 November 2008
• Published: 01 February 2009
• Issue Date: 12 March 2009
• DOI: https://doi.org/10.1038/nature07672