Conserved role of intragenic DNA methylation in regulating alternative promoters (original) (raw)

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Data deposits

Sequencing reads are available through the NCBI SRA, accession number SRP002318 (http://www.ncbi.nlm.nih.gov/sra/?term5SRP002318). Browser tracks (hg18 assembly) are available at http://genome.ucsc.edu/. The sequence data for the novel SHANK3 transcripts, 22t and 32t, have been deposited into the dbEST database (accession numbers GD253656 and GD253657, respectively).

References

1. Cokus, S. J. et al. Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning. Nature 452, 215–219 (2008)
   Article ADS CAS Google Scholar
2. Flanagan, J. M. & Wild, L. An epigenetic role for noncoding RNAs and intragenic DNA methylation. Genome Biol. 8, 307 (2007)
   Article Google Scholar
3. Lorincz, M. C., Dickerson, D. R., Schmitt, M. & Groudine, M. Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells. Nature Struct. Mol. Biol. (2004)
4. Ball, M. P. et al. Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nature Biotechnol. 27, 361–368 (2009)
   Article ADS CAS Google Scholar
5. Rauch, T. A. et al. A human B cell methylome at 100-base pair resolution. Proc. Natl Acad. Sci. USA 106, 671–678 (2009)
   Article ADS CAS Google Scholar
6. Eckhardt, F. et al. DNA methylation profiling of human chromosomes 6, 20 and 22. Nature Genet. 38, 1378–1385 (2006)
   Article CAS Google Scholar
7. Ching, T. T. et al. Epigenome analyses using BAC microarrays identify evolutionary conservation of tissue-specific methylation of SHANK3. Nature Genet. 37, 645–651 (2005)
   Article CAS Google Scholar
8. Illingworth, R. et al. A novel CpG island set identifies tissue-specific methylation at developmental gene loci. PLoS Biol. 6, e22 (2008)
   Article Google Scholar
9. Song, F. et al. Association of tissue-specific differentially methylated regions (TDMs) with differential gene expression. Proc. Natl Acad. Sci. USA 102, 3336–3341 (2005)
   Article ADS CAS Google Scholar
10. Weber, M. et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nature Genet. 37, 853–862 (2005)
    Article CAS Google Scholar
11. The FANTOM Consortium. The transcriptional landscape of the mammalian genome. Science 309, 1559–1563 (2005)
12. Carninci, P. et al. Genome-wide analysis of mammalian promoter architecture and evolution. Nature Genet. 38, 626–635 (2006)
    Article CAS Google Scholar
13. Kim, T. H. et al. A high-resolution map of active promoters in the human genome. Nature 436, 876–880 (2005)
    Article ADS CAS Google Scholar
14. Kapranov, P. et al. Examples of the complex architecture of the human transcriptome revealed by RACE and high-density tiling arrays. Genome Res. 15, 987–997 (2005)
    Article CAS Google Scholar
15. Kimura, K. et al. Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome Res. 16, 55–65 (2006)
    Article CAS Google Scholar
16. Meissner, A. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008)
    Article ADS CAS Google Scholar
17. Durand, C. M. et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genet. 39, 25–27 (2006)
    Article Google Scholar
18. Wilson, H. L. et al. Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. J. Med. Genet. 40, 575–584 (2003)
    Article CAS Google Scholar
19. Appanah, R. et al. An unmethylated 3′ promoter-proximal region is required for efficient transcription initiation. PLoS Genet. 3, e27 (2007)
    Article Google Scholar
20. Zhang, X. et al. Genome-wide high-resolution mapping and functional analysis of DNA methylation in Arabidopsis. Cell 126, 1189–1201 (2006)
    Article CAS Google Scholar
21. Lister, R. et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315–322 (2009)
    Article ADS CAS Google Scholar
22. Irizarry, R. A. et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nature Genet. 41, 178–186 (2009)
    Article CAS Google Scholar
23. Valen, E. et al. Genome-wide detection and analysis of hippocampus core promoters using DeepCAGE. Genome Res. 19, 255–265 (2009)
    Article CAS Google Scholar
24. Carninci, P. Tagging mammalian transcription complexity. Trends Genet. 22, 501–510 (2006)
    Article CAS Google Scholar
25. Affymetrix/Cold Spring Harbor Laboratory ENCODE Transcriptome Project. Post-transcriptional processing generates a diversity of 5′-modified long and short RNAs. Nature 457, 1028–1032 (2009)
26. Birol, I. et al. De novo transcriptome assembly with ABySS. Bioinformatics 25, 2872–2877 (2009)
    Article CAS Google Scholar
27. Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006)
    Article CAS Google Scholar
28. Walsh, C. P. & Bestor, T. H. Cytosine methylation and mammalian development. Genes Dev. 13, 26–34 (1999)
    Article CAS Google Scholar
29. Baylin, S. & Bestor, T. H. Altered methylation patterns in cancer cell genomes: cause or consequence? Cancer Cell 1, 299–305 (2002)
    Article CAS Google Scholar
30. Morin, R. D. et al. Profiling the HeLa S3 transcriptome using randomly primed cDNA and massively parallel short-read sequencing. Biotechniques 45, 81–94 (2008)
    Article CAS Google Scholar

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Acknowledgements

We thank S. Vandenberg for technical assistance and The Pleiades Promoter Project and their funders Genome Canada, Genome British Columbia, GlaxoSmithKline R&D Ltd, BC Mental Health and Addiction Services, Child & Family Research Institute, UBC Institute of Mental Health, and the UBC Office of the Vice President Research. This work was supported in part by an NIH NRSA-F31 fellowship to A.K.M. and an NIH NRSA-F32 fellowship to R.P.N., a grant from the National Brain Tumor Society and Goldhirsh Foundation to J.F.C., and by the British Columbia Cancer Foundation. T.W. was a Helen Hay Whitney Fellow and M.A.M. is a Terry Fox Young Investigator and a Michael Smith Senior Research Scholar.

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Author notes

1. Alika K. Maunakea & Ksenya Shchors
   Present address: Present addresses: Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland 20892, USA (A.K.M.); EPFL-ISREC, SV 2818, Station 19, Lausanne 1015, Switzerland (K.S.).,
2. Alika K. Maunakea and Raman P. Nagarajan: These authors contributed equally to this work.

Authors and Affiliations

1. Department of Neurosurgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, 94158, California, USA
   Alika K. Maunakea, Raman P. Nagarajan, Shaun D. Fouse, Brett E. Johnson, Chibo Hong & Joseph F. Costello
2. Genome Sciences Centre, BC Cancer Agency, 675 W. 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
   Mikhail Bilenky, Cletus D’Souza, Cydney Nielsen, Yongjun Zhao, Allen Delaney, Richard Varhol, Nina Thiessen, Steven J. M. Jones, Marco A. Marra & Martin Hirst
3. Center for Biomolecular Science and Engineering, University of California, Santa Cruz, 95064, California, USA
   Tracy J. Ballinger, David Haussler & Ting Wang
4. McGill Group for Suicide Studies, Douglas Hospital Research Centre, 6875 LaSalle Blvd, Verdun, Quebec H4H 1R3, Canada,
   Gustavo Turecki
5. Department of Pathology, University of California San Francisco, San Francisco, 94158, California, USA
   Ksenya Shchors
6. Department of Pediatrics and Institute for Regeneration Medicine, and Department of Neurological Surgery, University of California San Francisco, San Francisco, 94143, California, USA
   Vivi M. Heine & David H. Rowitch
7. Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University, St Louis, 63108, Missouri, USA
   Xiaoyun Xing, Chris Fiore, Maximiliaan Schillebeeckx & Ting Wang
8. Howard Hughes Medical Institute, University of California, Santa Cruz, 95064, California, USA
   David Haussler

Authors

1. Alika K. Maunakea
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2. Raman P. Nagarajan
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3. Mikhail Bilenky
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4. Tracy J. Ballinger
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5. Cletus D’Souza
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6. Shaun D. Fouse
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7. Brett E. Johnson
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8. Chibo Hong
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9. Cydney Nielsen
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10. Yongjun Zhao
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11. Gustavo Turecki
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12. Allen Delaney
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13. Richard Varhol
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14. Nina Thiessen
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15. Ksenya Shchors
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16. Vivi M. Heine
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17. David H. Rowitch
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18. Xiaoyun Xing
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19. Chris Fiore
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20. Maximiliaan Schillebeeckx
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21. Steven J. M. Jones
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22. David Haussler
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23. Marco A. Marra
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24. Martin Hirst
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25. Ting Wang
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26. Joseph F. Costello
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Contributions

A.K.M. conceived and performed SHANK3 experiments; R.P.N. designed and performed MeDIP-seq and MRE-seq and qRT-PCR; M.B., C.D., C.N., Y.Z., G.T. and S.J.M.J. performed and analysed brain ChIP-seq; M.A.M., M.H., Y.Z. supervised and analysed IGAII sequencing, and participated in project coordination; S.D.F. performed bisulphite sequencing. C.H. performed bisulphite sequencing and luciferase assay experiments; B.E.J. helped perform MRE-seq and bisulphite sequencing. A.D. wrote the script to parse the SMART and non-SMART containing tags from RNA-seq data. R.V. performed the iterative alignments from RNA-seq and N.T. generated the gene expression measures from the alignments. K.S., V.M.H. and D.H.R. performed mouse brain dissections and isolated astrocytes, neurons and neuronal precursors; T.W., T.J.B., X.X., C.F. and M.S. performed bioinformatics analyses. D.H. participated in project coordination and SHANK3 genomic conservation analysis. A.K.M., R.P.N., T.W. and J.F.C. coordinated the project, wrote the manuscript and incorporated revisions from co-authors.

Corresponding authors

Correspondence toTing Wang or Joseph F. Costello.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Tables 1-2, Supplementary Figures S1-S21 with legends, Supplementary Methods, which includes a Supplementary Table, Supplementary References and additional information for Supplementary Data 2. (PDF 5369 kb)

Supplementary Data 1

This file contains MeDIP and MRE datasets for 2 biological replicates. (XLS 3425 kb)

Supplementary Data 2

The file contains methylation analysis of transposable elements (see Supplementary Information file, page 60). (XLS 3851 kb)

Supplementary Data 3

This file contains bisulfite sequencing. (XLS 202 kb)

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Maunakea, A., Nagarajan, R., Bilenky, M. et al. Conserved role of intragenic DNA methylation in regulating alternative promoters.Nature 466, 253–257 (2010). https://doi.org/10.1038/nature09165

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• Received: 22 September 2009
• Accepted: 06 May 2010
• Issue Date: 08 July 2010
• DOI: https://doi.org/10.1038/nature09165