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

Nature volume 488, pages 116–120 (2012)Cite this article

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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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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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Author notes

  1. Yin Shen and Feng Yue: These authors contributed equally to this work.

Authors and Affiliations

  1. Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, California 92093-0653, USA ,

    Yin Shen, Feng Yue, David F. McCleary, Zhen Ye, Lee Edsall, Samantha Kuan, Ulrich Wagner, Jesse Dixon, Leonard Lee & Bing Ren

  2. Medical Scientist Training Program, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653, USA ,

    Jesse Dixon

  3. Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653, USA ,

    Jesse Dixon

  4. Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Twinbrook I NIAID Facility, Room 1417, 5640 Fishers Lane, Rockville, Maryland 20852, USA ,

    Victor V. Lobanenkov

  5. Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, Moores Cancer Center, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653, USA,

    Bing Ren

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  1. Yin Shen
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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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