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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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BackgroundAn Adversarial DNA N6-Methyladenine-Sensor Network Preserves Polycomb Silencing
Kweon, S.-M., Chen, Y., Moon, E., Kvederavičiūtė, K., Klimašauskas, S., & Feldman, D. E. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.03.018 · Cited by 168
Long-range enhancers regulating Myc expression are required for normal facial morphogenesis
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Epigenomic landscapes of retinal rods and cones
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“We next evaluated the levels of DNA methylation ( Lister et al., 2013 ) and histone modifications ( Shen et al., 2012 ) in fetal cerebral cortex and brain, respectively, which are rich sources of neural progenitors and immature neurons.”
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“001), which in wild-type cortex showed strong H3K4me1 enrichment, according to reference epigenomic maps from mouse cerebral cortex (Shen et al., 2012).”
BackgroundInfluentialWhat does our genome encode?Preprint
Stamatoyannopoulos, J. A. (2012) · Genome Research · doi:10.1101/gr.146506.112 · Cited by 120
“A new entry that promises to reshape the conservation conversation is The Mouse ENCODE Project, from which substantial data are already becoming available (Kim et al. 2012; The Mouse ENCODE Consortium 2012; Shen et al. 2012).”
BackgroundEGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity
Sun, Z., Xu, X., He, J., Murray, A., Sun, M.-A., Wei, X., Wang, X., McCoig, E., Xie, E., Jiang, X., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11905-3 · Cited by 152
DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias
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“To further confirm that loss of DNMT3A unveils enhancer sites, we generated maps of putative enhancers (Shen et al., 2013) based on H3K27ac and H3K4me1 histone peaks in leukemic FLT3-ITD and 3aKO/FLT3-ITD cells by ChIP-seq and DNAse1 hotspots from mouse ENCODE database (Consortium et al., 2012).”
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“Currently, 111,062 CTCF-binding sites in the mouse genome have been identified, with some being tissue specific and some ubiquitous (Shen et al., 2012).”
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“Regarding transcriptional regulation, enhancer–promoter interactions produced by looping might be limited to elements located within the same TAD [86].”
BackgroundConstructing 3D interaction maps from 1D epigenomes
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“Similar analyses of the coincidence of peaks with murine embryonic fibroblast enhancer (H3K4Me1, H3K4Me3 ) and bivalent enhancer (H3K4Me1, H3K27Ac) marks (Shen et al., 2012) revealed more than a 5-fold enrichment of Meis peaks with both enhancer and bivalent enhancer marks with respect to the whole genome and 2-fold w…”
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Kmt1e regulates a large neuron-specific topological chromatin domain
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“By examining a panel of histone modification ChIP-seq data in mouse tissues [43], we found that groups I and III DMVs are preferentially enriched for high CpGs (Additional file 1: Figure S3B) and H3K27me3 (Fig.”
Cooperative Action between SALL4A and TET Proteins in Stepwise Oxidation of 5-Methylcytosine
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Determinants of Receptor- and Tissue-Specific Actions in Androgen Signaling
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Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease
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“To determine which class the enhancer-associated ncRNAs described in the present study represent, we executed RNA-Seq on Poly(A) + RNA derived from differentiating mouse ESCs and integrated this with publicly available ChIP/RNA-Seq data sets [5,33].”
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“Enhancers recruit transcription factors (TFs) to regulate the transcription of target genes, often in a cell type-or tissue-speci fi c manner (Shen et al., 2012).”
BackgroundRecapitulation and reversal of schizophrenia-related phenotypes in Setd1a-deficient mice
Mukai, J., Cannavó, E., Crabtree, G., Sun, Z., Diamantopoulou, A., Thakur, P., Chang, C.-Y., Cai, Y., Lomvardas, S., Takata, A., et al. (2019) · bioRxiv · doi:10.1101/529701 · Cited by 125
“To assess if Setd1a-bound regulatory elements have pan-neuronal or cortical-specific functions we compared our H3K27ac ChIP-Seq from the PFC with ENCODE H3K27ac ChIP-Seq from the olfactory bulb (OB) and the cerebellum (Shen et al., 2012).”
MethodGenome-wide inference of natural selection on human transcription factor binding sites
Arbiza, L., Gronau, I., Aksoy, B. A., Hubisz, M. J., Gulko, B., Keinan, A., & Siepel, A. C. (2013) · Nature Genetics · doi:10.1038/ng.2658 · Cited by 131
An integrated chromatin accessibility and transcriptome landscape of human pre-implantation embryos
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“At the transcriptional level, expression of genes such as Emd and Gja1 is reduced as the heart matures.(42,43) Intriguingly, emerin (Emd) is known to function as a β-catenin–interacting protein that also modulates β-catenin intracellular localization.”
BackgroundKubo, N., Toh, H., Shirane, K., Shirakawa, T., Kobayashi, H., Sato, T., Sone, H., Sato, Y., Tomizawa, S.-I., Tsurusaki, Y., et al. (2015) · BMC Genomics · doi:10.1186/s12864-015-1833-5 · Cited by 145
“When published histone modification data from the adult testis [50] were analyzed, the DMRs of clusters 1 and 2 showed enrichment in enhancer marks such as histone H3 lysine-4 monomethylation (H3K4me1) and histone H3 lysine-27 acetylation (H3K27ac) [51, 52] (Fig.”
BackgroundMethodInfluentialChromatin-Driven Behavior of Topologically Associating Domains
Ciabrelli, F., & Cavalli, G. (2014) · Journal of Molecular Biology · doi:10.1016/j.jmb.2014.09.013 · Cited by 123
Griffon, A., Barbier, Q., Dalino, J., van Helden, J., Spicuglia, S., & Ballester, B. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku1280 · Cited by 126
A new class of temporarily phenotypic enhancers identified by CRISPR/Cas9-mediated genetic screening
Diao, Y., Li, B., Meng, Z., Jung, I., Lee, A. Y., Dixon, J., Maliskova, L., Guan, K.-L., Shen, Y., & Ren, B. (2016) · Genome Research · doi:10.1101/gr.197152.115 · Cited by 122
Self-citationAn inferred functional impact map of genetic variants in rice
Zhao, H., Li, J., Yang, L., Qin, G., Xia, C., Xu, X., Su, Y., Liu, Y., Ming, L., Chen, L., et al. (2021) · Molecular Plant · doi:10.1016/j.molp.2021.06.025 · Cited by 145
Kaminski, M. M., Tasić, J., Kresbach, C., Engel, H., Klockenbusch, J., Müller, A.-L., Pichler, R., Grahammer, F., Kretz, O., Huber, T. B., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3437 · Cited by 142
Massively parallel cis-regulatory analysis in the mammalian central nervous systemPreprint
Shen, S. Q., Myers, C. A., Hughes, A. E. O., Byrne, L. C., Flannery, J. G., & Corbo, J. C. (2015) · Genome Research · doi:10.1101/gr.193789.115 · Cited by 127
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“Recent genome-wide studies of transcription factor cistromes and histone modifications have highlighted the importance of distant enhancer sites in driving the cell type-specific gene regulation (Heintzman et al , 2009; Shen et al , 2012).”
A compendium and comparative epigenomics analysis of cis-regulatory elements in the pig genome
Zhao, Y., Hou, Y., Xu, Y., Luan, Y., Zhou, H., Qi, X., Hu, M., Wang, D., Wang, Z., Fu, Y., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22448-x · Cited by 169
An encyclopedia of enhancer-gene regulatory interactions in the human genome
Gschwind, A. R., Mualim, K. S., Karbalayghareh, A., Sheth, M. U., Dey, K. K., Jagoda, E., Nurtdinov, R. N., Xi, W., Tan, A. S., Jones, H., et al. (2023) · doi:10.1101/2023.11.09.563812 · Cited by 119
CTCF shapes chromatin structure and gene expression in health and disease
Dehingia, B., Milewska, M., Janowski, M., & Pękowska, A. (2022) · EMBO Reports · doi:10.15252/embr.202255146 · Cited by 141
“The observations that: (i) cognate and co-regulated enhancer – promoter pairs tend to reside in the same TAD (Shen et al , 2012; de Laat & Duboule, 2013; Symmons et al , 2014), (ii) disruption of TAD boundaries can result in aberrant gene expression of loci in the merged domains (Guo et al , 2015;…”
Tissue-Specific RNA Expression Marks Distant-Acting Developmental Enhancers
Wu, H., Nord, A. S., Akiyama, J. A., Shoukry, M. I., Afzal, V., Rubin, E. M., Pennacchio, L. A., & Visel, A. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004610 · Cited by 129
“To assess whether these TSTRs may represent in vivo enhancers, we first examined their evolutionary sequence constraint, a feature associated with many distant-acting enhancers [25,31,32].”
Low-affinity transcription factor binding sites shape morphogen responses and enhancer evolution
Ramos, A. I., & Barolo, S. (2013) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2013.0018 · Cited by 108
Divergent transcription is associated with promoters of transcriptional regulators
Lepoivre, C., Belhocine, M., Bergon, A., Griffon, A., Yammine, M., Vanhille, L., Cabeza, J. Z., Garibal, M., Koch, F., Maqbool, M. A., et al. (2013) · BMC Genomics · doi:10.1186/1471-2164-14-914 · Cited by 125
“To obtain a more general view of the functional relevance of LUAT-associated genes, we analyzed recently published directional and PolyA-enriched RNA-seq data from 17 mouse tissues [30].”
BackgroundThe genomic landscape of cohesin-associated chromatin interactions
DeMare, L. E., Leng, J., Cotney, J., Reilly, S. K., Yin, J., Sarro, R., & Noonan, J. P. (2013) · Genome Research · doi:10.1101/gr.156570.113 · Cited by 114
“Analysis of all SMC1A interactions suggest they show highly correlated patterns of H3K27ac marking across 19 embryonic and adult mouse tissues (Fig. 3B; Shen et al. 2012).”
BackgroundInfluentialContext-specific Polycomb mechanisms in development
Kim, J. J., & Kingston, R. E. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-022-00499-0 · Cited by 122
Lam, D. D., de Souza, F. S. J., Nasif, S., Yamashita, M., López‐Leal, R., Otero-Corchón, V., Meece, K., Sampath, H., Mercer, A. J., Wardlaw, S. L., et al. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1004935 · Cited by 120
Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation
Alder, O., Cullum, R., Lee, S., Kan, A. C., Wei, W., Yi, Y., Garside, V. C., Bilenky, M., Griffith, M., Morrissy, A. S., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.08.046 · Cited by 113
“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).”
BackgroundMethodInfluentialThe life history of retrocopies illuminates the evolution of new mammalian genesPreprint
Carelli, F. N., Hayakawa, T., Go, Y., Imai, H., Warnefors, M., & Kaessmann, H. (2016) · Genome Research · doi:10.1101/gr.198473.115 · Cited by 136
Minireview: Mechanisms of Growth Hormone-Mediated Gene Regulation
Chia, D. J. (2014) · Molecular Endocrinology · doi:10.1210/me.2014-1099 · Cited by 118
Single-cell nuclear architecture across cell types in the mouse brain
Takei, Y., Zheng, S., Yun, J., Shah, S., Pierson, N. G., White, J. A., Schindler, S., Tischbirek, C. H., Yuan, G., & Cai, L. (2021) · Science · doi:10.1126/science.abj1966 · Cited by 115
DNA methylation and chromatin accessibility profiling of mouse and human fetal germ cells
Guo, H., Hu, B., Yan, L., Yong, J., Wu, Y., Gao, Y., Guo, F., Hou, Y., Fan, X., Dong, J., et al. (2016) · Cell Research · doi:10.1038/cr.2016.128 · Cited by 129
An ATAC-seq atlas of chromatin accessibility in mouse tissues
Liu, C., Wang, M., Wei, X., Wu, L. L., Xu, J., Dai, X., Xia, J., Cheng, M., Yuan, Y., Zhang, P., et al. (2019) · Scientific Data · doi:10.1038/s41597-019-0071-0 · Cited by 118
Attenuated chromatin compartmentalization in meiosis and its maturation in sperm development
Alavattam, K. G., Maezawa, S., Sakashita, A., Khoury, H., Barski, A., Kaplan, N., & Namekawa, S. H. (2019) · Nature Structural & Molecular Biology · doi:10.1038/s41594-019-0189-y · Cited by 141
Genome-scale mutational signatures of aflatoxin in cells, mice, and human tumorsPreprint
Huang, M.-N., Yu, W., Teoh, W. W., Ardin, M., Jusakul, A., Ng, A., Boot, A., Abedi-Ardekani, B., Villar, S., Myint, S. S., et al. (2017) · bioRxiv · doi:10.1101/gr.220038.116 · Cited by 111
βlinc1 encodes a long noncoding RNA that regulates islet β-cell formation and functionPreprint
Arnes, L., Akerman, I., Balderes, D., Ferrer, J., & Sussel, L. (2016) · Genes & Development · doi:10.1101/gad.273821.115 · Cited by 111
“HiC analyses suggested that βlinc1 may be located at the edge of a TAD (Supplemental Fig. 11; Shen et al. 2012); however, the presence of this domain does not correlate with the observed in vivo gene expression changes.”
BackgroundInfluentialUesaka, M., Nishimura, O., Go, Y., Nakashima, K., Agata, K., & Imamura, T. (2014) · BMC Genomics · doi:10.1186/1471-2164-15-35 · Cited by 111
“For this analysis, we utilized processed data on mouse directional RNA-seq of 19 different tissues and primary cells available from NCBI Gene Expression Omnibus (GSE29278) [27,28].”
MethodKaaij, L. J. T., van de Wetering, M., Fang, F., Decato, B. E., Molaro, A., van de Werken, H. J. G., van Es, J. H., Schuijers, J., de Wit, E., de Laat, W. L., et al. (2013) · Genome biology · doi:10.1186/gb-2013-14-5-r50 · Cited by 118
Pugacheva, E. M., Rivero-Hinojosa, S., Espinoza, C. A., Méndez-Catalá, C. F., Kang, S., Suzuki, T., Kosaka-Suzuki, N., Robinson, S., Nagarajan, V., Ye, Z., et al. (2015) · Genome biology · doi:10.1186/s13059-015-0736-8 · Cited by 110
“With the advance of next-generation sequencing techniques, CTCF binding sites have been identified across fly, mouse, and human genomes [14, 16, 17].”
Self-citationTETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers
Charlton, J., Jung, E. J., Mattei, A. L., Bailly, N., Liao, J., Martin, E. J., Gießelmann, P., Brändl, B., Stamenova, E. K., Müller, F.-J., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0639-9 · Cited by 111
“We performed WGBS for WT and DKO cells at passage 4 and identified 3,888 DMRs that showed similar properties to human DKO-DMRs, with 82% overlapping putative somatic enhancers 36 .”
Terashima, M., Barbour, S., Ren, J., Yu, W., Han, Y., & Muegge, K. (2015) · Epigenetics · doi:10.1080/15592294.2015.1075691 · Cited by 141
“with active gene transcription.(44) The H3K4me1 pattern in both HFD and LFD samples displayed enrichment around TSS in a pattern that was distinct from the H3 retention pattern (Fig.”
BackgroundMethodInfluentialKann, M., Ettou, S. S., Jung, Y. L., Lenz, M. O., Taglienti, M. E., Park, P. J., Schermer, B., Benzing, T. R., & Kreidberg, J. A. (2015) · Journal of the American Society of Nephrology · doi:10.1681/asn.2014090940 · Cited by 123
Isolation and genome-wide characterization of cellular DNA:RNA triplex structures
Cetin, N. S., Kuo, C.-C., Ribarska, T., Li, R.-H., Costa, I., & Grummt, I. (2019) · Nucleic Acids Research · doi:10.1093/nar/gky1305 · Cited by 108
Mapping gene regulatory circuitry of Pax6 during neurogenesis
Thakurela, S., Tiwari, N., Schick, S., Garding, A., Ivánek, R., Berninger, B., & Tiwari, V. K. (2016) · Cell Discovery · doi:10.1038/celldisc.2015.45 · Cited by 136
Getting the genome in shape: the formation of loops, domains and compartments
Bouwman, B. A. M., & de Laat, W. L. (2015) · Genome biology · doi:10.1186/s13059-015-0730-1 · Cited by 115
“Bookmarking by CTCF, as described below, could contribute to constitutive looping, without necessarily yielding the typical enhancer signatures such as hypersensitivity [87] or histone acetylation [19] in unrelated tissues.”
BackgroundRobson, M. I., de las Heras, J. I., Czapiewski, R., Sivakumar, A., Kerr, A. R. W., & Schirmer, E. C. (2017) · Genome Research · doi:10.1101/gr.212308.116 · Cited by 107
“ximal through looping in three-dimensional space (Sanyal et al. 2012; Shen et al. 2012; Arner et al. 2015; Schoenfelder et al. 2015).”
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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