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A map of the cis-regulatory sequences in the mouse genome
Open accessAbstract
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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“Furthermore, an analysis of publically available DNase I hypersensitivity data (Shen et al., 2012) confirmed that >60% of embryonic sites remain accessible in the adult liver (data not shown).”
From Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation (2014) · cites this paper as Shen et al., 2012
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Holwerda, S. J. B., & de Laat, W. L. (2012) · Frontiers in Genetics · doi:10.3389/fgene.2012.00217 · Cited by 98
“The remainder is intronic and intergenic sequences, long considered to be junk DNA, but now realized to contain hundreds of thousands of sequence modules with the potential to regulate gene expression (Shen et al., 2012).”
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“…gene expression in hematopoiesis, we obtained similar results by assigning CRM targets as the most proximal gene and by using an alternative approach that defined ‘‘enhancer-promoter units (EPUs)’’ to predict CRM target genes independent of gene proximity (Shen et al. 2012; Wu et al. 2014).”
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“[75] (grey bar) are plotted next to enhancer probes that also contain a peak of either 5hmC (purple bar) or 5mC (red bar).”
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“%) of these peaks overlapped with annotated enhancer regions (Shen et al., 2012), defined as the 1Kb-vicinity of the reported center coordinate.”
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“For example, the regulatory elements in most genomes remain poorly annotated and require complex experimental methodologies for accurate identification (e.g. Shen et al. 2012).”
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“We compared unique H3K9ac and H3K4me3 peaks from WT and KO MEFs to an existing data set of CTCF peaks in MEFs to determine whether changes in histone marks could be specifically occurring near CTCFassociated chromatin boundaries [42].”
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“Raw files were downloaded from the National Centre for Biotechnology Information (NCBI) using the Sequencing Read Archive (SRA) Toolkit for 2-cell H3K4me3 ChIP-Seq [40] (GEO: GSE73952), MII oocyte H3K4me3 ChIP-Seq [41] (GEO: GSE71434), sperm ATAC-Seq [42] (GEO: GSE79230), 4-cell and morula ATAC-Seq [43] (NCBI SRA: SRP…”
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Physical clustering of FLC alleles during Polycomb-mediated epigenetic silencing in vernalizationPreprint
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“This understanding has been augmented by chromatin conformation capture techniques that have provided high-resolution interaction maps identifying topologically distinct domains within chromosomes (Noordermeer et al. 2011; Naumova et al. 2012; Shen et al. 2012).”
BackgroundReprogramming to Pluripotency Using Designer TALE Transcription Factors Targeting Enhancers
Gao, X., Yang, J. P., Tsang, J. C. H., Ooi, J., Wu, D., & Liu, P. (2013) · Stem Cell Reports · doi:10.1016/j.stemcr.2013.06.002 · Cited by 78
Transcriptional enhancers and their communication with gene promoters
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TADs and Their Borders: Free Movement or Building a Wall?
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Reorganization of 3D genome structure may contribute to gene regulatory evolution in primates
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“For example, 3D genome structures may bring linearly distant loci into close proximity, connecting genes with CREs [34-40].”
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An Activity-Mediated Transition in Transcription in Early Postnatal Neurons
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DNA Methylation is Developmentally Regulated for Genes Essential for Cardiogenesis
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“This is probably due to the fact that those enhancers were identified based largely on H3K4me1 modifications, which is enriched in both active and poised enhancers.(44,45) Next, we chose up to 14 ACGT sites with a range of different tag counts, representing 0%, 25%, 50%, 75%, or 100% methylation by massively parallel…”
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Jmjd3-Mediated H3K27me3 Dynamics Orchestrate Brown Fat Development and Regulate White Fat Plasticity
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“Indeed, if we used fold change of 5 as a cutoff for BAT-selective genes, we found that most of the new genes are also expressed with a high level in other tissues by crossexamining with published RNA-Seq datasets (Shen et al., 2012).”
Deciphering the Epigenetic Code of Cardiac Myocyte Transcription
Preißl, S., Schwaderer, M., Raulf, A., Hesse, M., Grüning, B. A., Köbele, C., Backofen, R., Fleischmann, B. K., Hein, L., & Gilsbach, R. (2015) · Circulation Research · doi:10.1161/circresaha.115.306337 · Cited by 75
“Enriched GO terms of the category biological process were identified by ClueGO.17 Results”
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Evolution of transcriptional enhancers and animal diversity
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Molecular hyperdiversity and evolution in very large populations
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“Despite rapid progress in mapping regulatory interactions between TFs and their targets (Gerstein et al. 2010; Negre et al. 2011; Niu et al. 2011; Shen et al. 2012), the identification of cis-regulatory response elements (CRE) within genomes still presents a major challenge.”
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“DNA methylation: human liver (73), bovine lung (74), porcine CCs (this study), rat left ventricle (75), and mouse cerebellum (76); H3K4me3 and H3K27me3: human liver (73), bovine CCs, porcine CCs, rat CCs (this study), and mouse cerebellum (77).”
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“For instance, within TADs, promoters and enhancers have been found to form ~100 kb co-regulated clusters 2 .”
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“Enhancer-gene interactions occur primarily within topologically associating domains (TADs) that spatially constrain them (Dixon et al., 2012; Shen et al., 2012; Nora et al., 2012).”
Understanding the regulatory and transcriptional complexity of the genome through structurePreprint
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“Additional structures, including histone locus bodies, stress bodies, and other epigenetic bodies also require RNA for assembly (Shevtsov and Dundr 2011), anticipating a broader role for RNA in subnuclear organization.”
BackgroundEpigenetic layers and players underlying neurodevelopment
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Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons
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“Discrete regions with low levels of DNA methylation have previously been found to indicate TF binding (Mo et al., 2015; Schultz et al., 2015; Stadler et al., 2011).”
BackgroundEmergence of the Noncoding Cancer Genome: A Target of Genetic and Epigenetic Alterations
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“5 GT H3K27ac datasets as well as 9 published H3K27ac datasets collected from a range of limb stages (Cotney et al., 2012; Cotney et al., 2013; Shen et al., 2012).”
BackgroundMethodInfluentialLarge-Scale Identification of Coregulated Enhancer Networks in the Adult Human Brain
Vermunt, M. W., Reinink, P., Korving, J., de Bruijn, E., Creyghton, P. M., Başak, O., Geeven, G., Toonen, P. W., Lansu, N. R., Meunier, C., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.09.023 · Cited by 86
“However, this analysis underrepresents the total amount of enhancers found by an order of magnitude (Shen et al., 2012; Zhu et al., 2013).”
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“Homozygous Tal1-null murine embryos die of anemia with failed yolk sac hematopoiesis (Robb et al. 1995; Shivdasani et al. 1995).”
BackgroundS-adenosylmethionine Levels Regulate the Schwann Cell DNA Methylome
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“Interestingly, putative enhancers (identified by presence of H3K4me1) (Shen et al., 2012) and repeat regions were significantly enriched (Figure 1G).”
3C and 3C-based techniques: the powerful tools for spatial genome organization deciphering
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Chromatin and RNA Maps Reveal Regulatory Long Noncoding RNAs in Mouse
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Gain of CTCF-Anchored Chromatin Loops Marks the Exit from Naive Pluripotency
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“Likewise, expression patterns of genes encompassed within a TAD are significantly correlated (Shen et al., 2012; Zhan et al., 2017).”
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“TADs are 3D structures with enriched intra-domain interactions that tend to insulate genes and their regulatory elements [13].”
Background
Metadata
- Authors
- Shen, Y., Yue, F., McCleary, D. F., Ye, Z., Edsall, L., Kuan, S., Wagner, U., Dixon, J., Lee, L., Lobanenkov, V. V., & Ren, B.
- Affiliations
- Ludwig Cancer Research (US)
- University of California San Diego (US)
- National Institutes of Health (US)
- Corresponding author
- Ren, Bing
- ORCID
- Venue
- Nature
- Published
- 2012-07-01
- Volume
- 488
- Issue
- 7409
- Pages
- 116-120
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4041622
- OpenAlex
- W2042930277
- Cited by
- 1,361
- References
- 29
- Citations by year
- 2026: 12 · 2025: 24 · 2024: 51 · 2023: 75 · 2022: 88 · 2021: 119 · 2020: 90 · 2019: 107 · 2018: 97 · 2017: 110 · 2016: 125 · 2015: 137 · 2014: 167 · 2013: 132 · 2012: 26
- FWCI
- 59.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Human Genome Research Institute (R01HG003991)
- National Institute of General Medical Sciences (T32GM007198)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- cis-regulatory sequences, mouse genome, enhancers, promoter, CTCF binding sites, tissue-specific gene expression, transcription factor binding, conserved non-coding elements, genome annotation, ChIP-seq
- MeSH terms
- Acetylation, Animals, Chromatin, Enhancer Elements, Genetic, Gene Expression Regulation, Male, Methylation, Mice, Inbred C57BL, Organ Specificity, Promoter Regions, Genetic, Regulatory Sequences, Nucleic Acid, Transcription Factors, Genome, Conserved Sequence, Sequence Analysis, DNA, Evolution, Molecular, Physical Chromosome Mapping, Chromatin Immunoprecipitation, Mice, Molecular Sequence Annotation, Nucleotide Motifs
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