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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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“%) connect to an active regulatory region before treatment, based on H3K27Ac enrichment (Shen et al., 2012).”
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“Ndufs2 is ubiquitously expressed and essential for CI activity, whereas Cox4i2 expression is limited to several tissues, including the lung, placenta, heart, tongue, breast, and adipose tissue ( Shen et al., 2012 ; Uhlén et al., 2015 ; Figure 1—figure supplement 1A–”
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Directed Evolution of an Enhanced POU Reprogramming Factor for Cell Fate Engineering
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“Likewise, when inspecting the subset of sites annotated as MEF enhancers (Shen et al. 2012), we found that Oct4 and ePOU alone induced minimal changes but given the presence of Sox2 or Klf4, ePOU accelerated the closing of these somatic sites (supplementary fig.”
BackgroundProfiling the circulating mRNA transcriptome in human liver disease
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“Many genes are under control of multiple enhancers that activate transcription in the same cell type (Osterwalder et al., 2018; Shen et al., 2012).”
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“Moreover, animal models may not elicit the expected functional impact of human variations([92]) because regulatory variants are often species-specifi c([93]).”
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“Recent estimations indicate that ~90% of disease and trait-associated variants occur within non-coding sequences, a large number of which may correspond to regulatory elements (30,33,34).”
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Genetic evidence for conserved non-coding element function across species–the ears have it
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“Such genome-wide analyses of the human and mouse chromatin landscapes in several cell types are now accessible in searchable databases (Ernst et al., 2011; Shen et al., 2012).”
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Between form and function: the complexity of genome folding
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Epigenetic inheritance is unfaithful at intermediately methylated CpG sites
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A Myb enhancer-guided analysis of basophil and mast cell differentiation
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“Several studies have reported distinct TF-binding preferences between enhancers and promoters (Rada-Iglesias et al. 2011; Shen et al. 2012; Thurman et al. 2012; Core et al. 2014; Nguyen et al. 2016), and some of these differences may be due to differences in GC content (Andersson et al. 2014).”
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“Presence of CTCF binding sites in the same domain of enhancer and promoter of the PCG blocks the interaction between these regulatory elements of the genome (31).”
BackgroundMethodFrom association to mechanism in complex disease genetics: the role of the 3D genome
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Quantitative differences in TAD border strength underly the TAD hierarchy in Drosophila chromosomes
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“In contrast, H3K27ac was present at all active promoter classes, regardless of cell-type specificity, which is consistent with the association of this histone mark with transcriptional elongation (Stasevich et al. 2014).”
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“It is widely established that enhancers may act over very large distances and interact with multiple promoters [25,47,48], and activation through this mechanism has been described for some LTRs as well as non-LTR repeats [40,49-51].”
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“Next, we linked the enhancers with their target genes using the mouse cis-regulatory atlas [38].”
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Loops and the activity of loop extrusion factors constrain chromatin dynamics
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Pluripotency factors regulate the onset of Hox cluster activation in the early embryo
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Cis-regulatory determinants of MyoD function
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“Genome-wide binding data of transcription factor occupancy together with high-resolution mapping of various regulatory histone marks have provided an extensive catalog of CREs in mice and human (11,12).”
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Epigenetics and Evolution: Transposons and the Stochastic Epigenetic Modification Model
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“Enhancers act at a distance, are often epigenetically modified, and the modification is changed during development [36].”
BackgroundChromatin Dynamics during Differentiation of Myeloid Cells
Schönheit, J., Leutz, A., & Rosenbauer, F. (2014) · Journal of Molecular Biology · doi:10.1016/j.jmb.2014.08.015 · Cited by 15
Almenar-Queralt, A., Kim, S., Benner, C., Herrera, C., Kang, D. E., Garcia-Bassets, I., & Goldstein, L. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.513705 · Cited by 15
LincRNA‐EPS impairs host antiviral immunity by antagonizing viral RNA–PKR interaction
Zhu, J., Chen, S.-C., Sun, L.-Q., Liu, S.-Y., Bai, X., Li, D.-P., Zhang, F., Qiao, Z., Li, L., Yao, H.-P., et al. (2022) · EMBO Reports · doi:10.15252/embr.202153937 · Cited by 14
Multiple parameters shape the 3D chromatin structure of single nuclei at the doc locus in Drosophila
Götz, M., Messina, O., Espínola, S., Fiche, J.-B., & Nöllmann, M. (2022) · Nature Communications · doi:10.1038/s41467-022-32973-y · Cited by 16
“TADs often encapsulate cis -regulatory elements (CREs), thereby facilitating interactions between enhancers and promoters that are critical for transcriptional regulation 6–11 .”
Gizzi, A. M. C. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.780822 · Cited by 13
“One spatial genomics study was able to establish a “chromatin profile” based on the multiplexed detection of several histone marks at specific DNA locus that matched ChIP-seq (Shen et al., 2012) or SPRITE measurements (Quinodoz et al., 2018) at 1-Mb resolution, but in this case with single-cell information.”
BackgroundInfluentialInference of 3D genome architecture by modeling overdispersion of Hi-C data
Varoquaux, N., Noble, W. S., & Vert, J. (2023) · Bioinformatics · doi:10.1093/bioinformatics/btac838 · Cited by 16
“DNA in vivo is folded in three dimensions, and this 3D structure plays an important role in many biological functions, including gene regulation, DNA replication, and DNA repair (De and Michor, 2011; Dixon et al. , 2012; Ryba et al. , 2010; Shen et al. , 2012).”
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Neonatal thyroxine activation modifies epigenetic programming of the liver
Fonseca, T. L., Garcia, T., Fernandes, G. W., Nair, T. M., & Bianco, A. C. (2021) · Nature Communications · doi:10.1038/s41467-021-24748-8 · Cited by 24
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Differentially Methylated Super-Enhancers Regulate Target Gene Expression in Human Cancer
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Deconvolving sequence features that discriminate between overlapping regulatory annotations
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“If we had used analysis methods that rely on mutually exclusive categories, we would need to restrict analysis to ~97,000 sites labeled as either shared or exclusive to one of the six cell types (Shen et al , 2012).”
MethodÄijö, T., Huang, Y., Mannerström, H., Chávez, L., Tsagaratou, A., Rao, A., & Lähdesmäki, H. J. (2016) · Genome biology · doi:10.1186/s13059-016-0911-6 · Cited by 18
“Intriguingly, these loci reside in the vicinity of a promoter of a long non-coding gene, Pvt1 (plasmacytoma variant translocation 1; Figure S10c in Additional file 4) and an intronic enhancer within Igsf21 (immunoglobin superfamily, member 21; Figure S10a in Additional file 4) identified in mESCs [51].”
BackgroundESCI award lecture: regulation, function and biomarker potential of DNA methylation
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The Persistent Contributions of RNA to Eukaryotic Gen(om)e Architecture and Cellular FunctionPreprint
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Malt, A. L., Cesario, J. M., Tang, Z., Brown, S. M., & Jeong, J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.592014 · Cited by 13
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“7 , 30 , 31 Mapping and comparing epigenomes during a developmental or a differentiation process has become a popular experimental approach.”
BackgroundRecruitment of Transcription Complexes to Enhancers and the Role of Enhancer Transcription
Stees, J. R., Varn, F., Huang, S., Strouboulis, J., & Bungert, J. (2012) · Biology · doi:10.3390/biology1030778 · Cited by 10
“A recent map of cis-regulatory DNA elements in the mouse genome suggests that the number of enhancers far exceeds the number of genes [6].”
BackgroundEfficient and Accurate Detection of Topologically Associating Domains from Contact Maps
Ardakany, A. R., & Lonardi, S. (2017) · Workshop on Algorithms in Bioinformatics · doi:10.4230/lipics.wabi.2017.22 · Cited by 14
Giorgetti, L., Piolot, T., & Heard, É. (2014) · Methods in molecular biology · doi:10.1007/978-1-4939-2253-6_3 · Cited by 11
Interaction of methyl-CpG-binding protein 2 (MeCP2) with distinct enhancers in the mouse cortex
Mishra, G. P., Sun, E. X., Chin, T., Eckhardt, M., Greenberg, M. E., & Stroud, H. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01808-y · Cited by 15
“We correlated the MBH sites with several ENCODE brain ChIP–seq datasets 28 and confirmed that MBH sites most significantly correlated with H3K27ac and CTCF binding sites, genomic features that are implicated in enhancer regulation (Supplementary Fig.”
Artificial selection footprints in indigenous and commercial chicken genomes
Wu, S.-W., Dou, T.-F., Wang, K., Yuan, S.-S., Yan, S.-X., Xu, Z., Liu, Y., Jian, Z.-H., Zhao, J., Zhao, R., et al. (2024) · BMC Genomics · doi:10.1186/s12864-024-10291-5 · Cited by 13
“Therefore, it is pressing to map out the cis -regulatory elements in the chicken reference genome as has been done for C. elegans [83, 84], D. melanogaster [83, 85], mice [86, 87] and humans [87, 88].”
BackgroundTranscriptional regulation of the thymus master regulator Foxn1
Kadouri, N., Givony, T., Nevo, S., Hey, J., Ben-Dor, S., Damari, G., Dassa, B., Dobeš, J., Weichenhan, D., Bähr, M., et al. (2022) · Science immunology · doi:10.1126/sciimmunol.abn8144 · Cited by 13
“Therefore, to map possible CTCF binding sites in the Foxn1 locus, we analyzed publicly available CTCF chromatin immunoprecipitation sequencing (ChIP-seq) datasets for tissues that do not express Foxn1 (45) in addition to mTEChi (Fig.”
MethodBoyling, A., Pérez‐Siles, G., & Kennerson, M. L. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.842860 · Cited by 15
“However, co-cultures and 3D organoid systems are becoming increasingly useful for establishing cellular interactions and creating 3D microenvironments that more closely resemble in vivo development (Shi et al., 2017; Lee et al., 2020).”
BackgroundGilbertson, S. E., & Weinmann, A. S. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.10.007 · Cited by 12
A myocardin-adjacent lncRNA balances SRF-dependent gene transcription in the heartPreprint
Anderson, D. M., Anderson, K. M., Nelson, B. R., McAnally, J., Bezprozvannaya, S., Shelton, J. M., Bassel‐Duby, R., & Olson, E. N. (2021) · Genes & Development · doi:10.1101/gad.348304.121 · Cited by 16
“Promoter-specific H3K4Me3 histone modifications demarcate a single promoter site for CARDINAL in the developing and adult mouse heart (Supplemental Fig. S1A; Shen et al. 2012).”
BackgroundBarth, N. K. H., Li, L., & Taher, L. (2020) · Genome Biology and Evolution · doi:10.1093/gbe/evaa004 · Cited by 24
Landscape of Enhancer-Enhancer Cooperative Regulation during Human Cardiac Commitment
Chen, H., Xiao, J. Y., Shao, T., Wang, L., Bai, J., Li, X., Ding, N., Qu, Y., Tian, Y., Chen, X., et al. (2019) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2019.07.015 · Cited by 18
“For example, Shen et al.13 predicted enhancer-promoter pairs based on the correlation of the chromatin state at enhancer and the RNA polymerase II (Pol II) intensity at promoter for each possible pair of elements along a chromosome.”
BackgroundLarge-scale 3D chromatin reconstruction from chromosomal contacts
Zhang, Y., Liu, W., Lin, Y., Ng, Y. K., & Li, S. C. (2019) · BMC Genomics · doi:10.1186/s12864-019-5470-2 · Cited by 13
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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