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. 2012 Aug 2;488(7409):116-20.
doi: 10.1038/nature11243.

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

Yin Shen  1 , Feng Yue, David F McCleary, Zhen Ye, Lee Edsall, Samantha Kuan, Ulrich Wagner, Jesse Dixon, Leonard Lee, Victor V Lobanenkov, Bing Ren
Affiliations

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

Yin Shen et al. Nature. .

Abstract

The laboratory mouse is the most widely used mammalian model organism in biomedical research. The 2.6 × 10(9) bases of the mouse genome possess a high degree of conservation with the human genome, 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 sequences, 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 elegans. 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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Conflict of interest statement

The authors declare no competing financial interests. Readers are welcome to comment on the online version of this article at www.nature.com/nature.

Figures

Figure 1
Figure 1. Identification of cis-regulatory elements in the mouse genome
a, UCSC genome browser views of ChIP-Seq and RNA-Seq data for mESC, heart and liver (chromosome 4). The values on the y axis for ChIP-Seq data are input normalized intensities. kb, kilobases. b, An overview of the predicted regulatory elements in the 19 tissue and cell types. E14.5, embryonic day 14.5; MEF, murine embryonic fibroblast. c, Percentages of known cis-regulatory elements recovered in this study.
Figure 2
Figure 2. Evolutionary conservation of the identified cis-regulatory elements
a, Evolutionary conservation of cis-regulatory elements, in comparison with exons and random genomic sequences. Asterisk, P < 0.001, Fisher's exact test. b, UCSC genome browser views of chromatin state and CTCF-binding sites at Sox2 loci for mESCs and human ESCs (hESCs) on chromosome 3. DNA sequences, chromatin states and CTCF binding are all conserved in this region. c, Number of hESC regulatory elements that are conserved and predicted as regulatory elements in mESCs. d, Number of mESC regulatory elements that are conserved and predicted as regulatory elements in hESCs. e, Functional annotation of the conserved non-coding sequences based on the cis-regulatory elements identified in this study. The asterisk in c, d and e indicates CTCF-binding sites that do not overlap with either promoters or enhancers.
Figure 3
Figure 3. Genomic organization of co-regulated promoters and enhancers
a, Tissue specificity of the usages of promoters (H3K4me3 and polII), enhancers (H3K4me1) and CTCF-binding sites. b, Distribution of the Spearman correlation coefficient of H3K4me1 at enhancers and polII at promoters of random permutation, the nearest TSS model, and the CTCF block model. c, Enhancers and promoters form co-regulated clusters of different sizes, as shown by the Spearman correlation coefficient of H3K4me1 at enhancers and polII at promoters on chromosome 19. d, Hi-C interaction heatmap showing that the physical partitioning of the genome is highly correlated with the EPUs that encompass Pcdhα, Pcdhβ and Pcdhγ gene clusters on chromosome 18. Top: normalized Hi-C interaction frequencies in mouse cortex as a two-dimensional heatmap. Bottom: UCSC genome browser views of the same regions, including the identified EPUs and the ChIP-Seq data (H3K27ac, H3K4me1, H3K4me3, polII and CTCF) in cortex. e, The average normalized Hi-C interaction frequencies for enhancer–promoter pairs within EPUs, between EPUs, and expected by random chance.
Figure 4
Figure 4. Motif analysis of tissue-specific enhancers
a, Classification of development stage-specific enhancers based on their chromatin state (H3K4me1) between embryonic (embryonic day 14.5; E14.5) and adult brain. b and c, Gene Ontology analysis for the genes associated with embryonic brain-specific enhancers and adult cortex-specific enhancers. d, Classification of tissue-specific enhancers on the basis of their chromatin state (H3K4me1) among different tissue and cell types. The first 19 tissue-specific clusters were used for further motif analysis. The last cluster contains enhancers enriched in multiple tissues with no clear patterns. e, Enrichment of three transcription factor recognition motifs in the predicted enhancers. REST, RE1-silencing transcription factor. f, Heatmap showing the clustering of 270 transcription factor motifs on the basis of their enrichment in the various groups of enhancers as identified in e.g, Boxplot showing that the de novo motifs found in tissue-specific enhancers are evolutionarily conserved. h–k, Examples of motifs that show high sequence conservation: h, REST motif in cortex-specific enhancers; i, Hnf1 motif in kidney-specific enhancers; j, Oct4 motif in mESC-specific enhancers; k, Atoh1 motif in cerebellum-specific enhancers.
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