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A map of the cis-regulatory sequences in the mouse genome

Abstract

The laboratory mouse is the most widely used mammalian model organism in biomedical research. The 2.6 × 109 bases of the mouse genome possess a high degree of conservation with the human genome1, so a thorough annotation of the mouse genome will be of significant value to understanding the function of the human genome. So far, most of the functional sequences in the mouse genome have yet to be found, and the cis-regulatory sequences in particular are still poorly annotated. Comparative genomics has been a powerful tool for the discovery of these sequences2, but on its own it cannot resolve their temporal and spatial functions. Recently, ChIP-Seq has been developed to identify cis-regulatory elements in the genomes of several organisms including humans, Drosophila melanogaster and Caenorhabditis elegans3,4,5. Here we apply the same experimental approach to a diverse set of 19 tissues and cell types in the mouse to produce a map of nearly 300,000 murine cis-regulatory sequences. The annotated sequences add up to 11% of the mouse genome, and include more than 70% of conserved non-coding sequences. We define tissue-specific enhancers and identify potential transcription factors regulating gene expression in each tissue or cell type. Finally, we show that much of the mouse genome is organized into domains of coordinately regulated enhancers and promoters. Our results provide a resource for the annotation of functional elements in the mammalian genome and for the study of mechanisms regulating tissue-specific gene expression.

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Figure 1: Identification of cis -regulatory elements in the mouse genome.
Figure 2: Evolutionary conservation of the identified cis -regulatory elements.
Figure 3: Genomic organization of co-regulated promoters and enhancers.
Figure 4: Motif analysis of tissue-specific enhancers.

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Gene Expression Omnibus

References

  1. Waterston, R. H. et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002)

    Article  ADS  CAS  Google Scholar 

  2. Visel, A., Rubin, E. M. & Pennacchio, L. A. Genomic views of distant-acting enhancers. Nature 461, 199–205 (2009)

    Article  ADS  CAS  Google Scholar 

  3. The ENCODE Project Consortium. A user’s guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol. 9. e1001046 (2011)

  4. Gerstein, M. B. et al. Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project. Science 330, 1775–1787 (2010)

    Article  ADS  CAS  Google Scholar 

  5. Roy, S. et al. Identification of functional elements and regulatory circuits by Drosophila modENCODE. Science 330, 1787–1797 (2010)

    Article  ADS  CAS  Google Scholar 

  6. Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007)

    Article  CAS  Google Scholar 

  7. Creyghton, M. P. et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl Acad. Sci. USA 107, 21931–21936 (2010)

    Article  ADS  CAS  Google Scholar 

  8. 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 

  9. Rada-Iglesias, A. et al. A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470, 279–283 (2011)

    Article  ADS  CAS  Google Scholar 

  10. Heintzman, N. D. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459, 108–112 (2009)

    Article  ADS  CAS  Google Scholar 

  11. Heintzman, N. D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nature Genet. 39, 311–318 (2007)

    Article  CAS  Google Scholar 

  12. Kim, T. H. et al. Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell 128, 1231–1245 (2007)

    Article  CAS  Google Scholar 

  13. Visel, A. et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854–858 (2009)

    Article  ADS  CAS  Google Scholar 

  14. Parkhomchuk, D. et al. Transcriptome analysis by strand-specific sequencing of complementary DNA. Nucleic Acids Res. 37, e123 (2009)

    Article  Google Scholar 

  15. Pruitt, K. D., Tatusova, T. & Maglott, D. R. NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res. 35, D61–D65 (2007)

    Article  CAS  Google Scholar 

  16. Visel, A., Minovitsky, S., Dubchak, I. & Pennacchio, L. A. VISTA Enhancer Browser—a database of tissue-specific human enhancers. Nucleic Acids Res. 35, D88–D92 (2007)

    Article  CAS  Google Scholar 

  17. Chen, X. et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133, 1106–1117 (2008)

    Article  CAS  Google Scholar 

  18. Schmidt, D. et al. Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding. Science 328, 1036–1040 (2010)

    Article  ADS  CAS  Google Scholar 

  19. Birney, E. et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447, 799–816 (2007)

    Article  ADS  CAS  Google Scholar 

  20. Siepel, A. et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 15, 1034–1050 (2005)

    Article  CAS  Google Scholar 

  21. Ernst, J. et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43–49 (2011)

    Article  ADS  CAS  Google Scholar 

  22. Li, G. et al. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148, 84–98 (2012)

    Article  CAS  Google Scholar 

  23. Ong, C. T. & Corces, V. G. Enhancer function: new insights into the regulation of tissue-specific gene expression. Nature Rev. Genet. 12, 283–293 (2011)

    Article  CAS  Google Scholar 

  24. Kagey, M. H. et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 467, 430–435 (2010)

    Article  ADS  CAS  Google Scholar 

  25. Splinter, E. et al. CTCF mediates long-range chromatin looping and local histone modification in the β-globin locus. Genes Dev. 20, 2349–2354 (2006)

    Article  CAS  Google Scholar 

  26. Nora, E. P. et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485, 381–385 (2012)

    Article  ADS  CAS  Google Scholar 

  27. Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012)

    Article  ADS  CAS  Google Scholar 

  28. Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009)

    Article  ADS  CAS  Google Scholar 

  29. Chepelev, I., Wei, G., Wangsa, D., Tang, Q. & Zhao, K. Characterization of genome-wide enhancer–promoter interactions reveals co-expression of interacting genes and modes of higher order chromatin organization. Cell Res. 22, 490–503 (2012)

    Article  CAS  Google Scholar 

  30. Hawkins, R. D. et al. Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell 6, 479–491 (2010)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank F. Jin, Y. Luu, S. Klugman, A. Y.-J. Kim, Q.-M. Ngo, B. A. Gomez and S. Selvaraj for consultation. The mESC line Bruce4 was a gift from UCSD Transgenic Core. Research funding was provided by the National Human Genome Research Institute (R01HG003991) and the Ludwig Institute for Cancer Research to B.R. Y.S. is supported by a postdoctoral fellowship from the International Rett Syndrome Foundation. J.D. is supported by a pre-doctoral fellowship from the California Institute for Regenerative Medicine.

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Authors and Affiliations

Authors

Contributions

Y.S., F.Y. and B.R. designed the experiments. Y.S., D.M., Z.Y. and L.L. conducted experiments. F.Y. performed computational analysis. U.W. contributed to RNA-Seq data analysis. J.D. contributed to Hi-C data analysis. S.K. and L.E. performed DNA sequencing and initial data processing. V.L. provided CTCF monoclonal antibodies. Y.S., F.Y. and B.R. prepared the manuscript.

Corresponding author

Correspondence to Bing Ren.

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Competing interests

The authors declare no competing financial interests.

Additional information

Data sets are available from the ENCODE website (http://genome.ucsc.edu/ENCODE), the supporting website for this paper (http://chromosome.sdsc.edu/mouse/index.html) and the Gene Expression Omnibus (GSE29184).

Supplementary information

Supplementary Information

This file contains Supplementary Text, Supplementary References, Supplementary Figures 1-16 and Supplementary Tables 1-3, 6, 8 and 11-16 - see separate zipped file for Supplementary Tables 4, 5, 7 and 9-10. (PDF 5454 kb)

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Shen, Y., Yue, F., McCleary, D. et al. A map of the cis-regulatory sequences in the mouse genome. Nature 488, 116–120 (2012). https://doi.org/10.1038/nature11243

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