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Histone modifications at human enhancers reflect global cell-type-specific gene expression
Open accessAbstract
The human body is composed of diverse cell types with distinct functions. Although it is known that lineage specification depends on cell-specific gene expression, which in turn is driven by promoters, enhancers, insulators and other cis-regulatory DNA sequences for each gene, the relative roles of these regulatory elements in this process are not clear. We have previously developed a chromatin-immunoprecipitation-based microarray method (ChIP-chip) to locate promoters, enhancers and insulators in the human genome. Here we use the same approach to identify these elements in multiple cell types and investigate their roles in cell-type-specific gene expression. We observed that the chromatin state at promoters and CTCF-binding at insulators is largely invariant across diverse cell types. In contrast, enhancers are marked with highly cell-type-specific histone modification patterns, strongly correlate to cell-type-specific gene expression programs on a global scale, and are functionally active in a cell-type-specific manner. Our results define over 55,000 potential transcriptional enhancers in the human genome, significantly expanding the current catalogue of human enhancers and highlighting the role of these elements in cell-type-specific gene expression.
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“ChIPseq using antibodies to H3K4Me3, a mark associated with active promoter sites (Ernst et al., 2011), and to H3K27Ac, a mark associated with enhancer elements (Heintzman et al., 2009), demonstrated mapped read peaks corresponding to at least four major transcriptional start sites within the SYNE1 locus (P1–P4), one of which (P3) lies immediately upstream of the p.L3206M mutation (Figure 3E).”
From Using Whole-Exome Sequencing to Identify Inherited Causes of Autism (2013) · cites this paper as Heintzman et al., 2009
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Cites
High-Resolution Profiling of Histone Methylations in the Human Genome
Barski, A., Cuddapah, S., Cui, K., Roh, T.-Y., Schones, D. E., Wang, Z., Wei, G., Chepelev, I., & Zhao, K. (2007) · Cell · doi:10.1016/j.cell.2007.05.009 · Cited by 6,845
Heintzman, N. D., Stuart, R. K., Hon, G., Fu, Y., Ching, C. W., Hawkins, R. D., Barrera, L. O., Van Calcar, S., Qu, C., Ching, K. A., et al. (2007) · Nature Genetics · doi:10.1038/ng1966 · Cited by 3,398 · cited 7×
“Using previously described chromatin signatures for enhancers 5 , we predicted 36,589 enhancers in the HeLa genome (Fig.”
MethodInfluentialSelf-citationGenome-Wide Mapping of in Vivo Protein-DNA Interactions
Johnson, D. S., Mortazavi, A., Myers, R. M., & Wold, B. (2007) · Science · doi:10.1126/science.1141319 · Cited by 2,927
The ENCODE (ENCyclopedia Of DNA Elements) Project
(2004) · Science · doi:10.1126/science.1105136 · Cited by 2,390
Xie, X., Lu, J., Kulbokas, E. J., Golub, T. R., Mootha, V., Lindblad-Toh, K., Lander, E. S., & Kellis, M. (2005) · Nature · doi:10.1038/nature03441 · Cited by 1,872
Self-citationRobertson, G., Hirst, M., Bainbridge, M., Bilenky, M., Zhao, Y., Zeng, T., Euskirchen, G., Bernier, B., Varhol, R., Delaney, A., et al. (2007) · Nature Methods · doi:10.1038/nmeth1068 · Cited by 1,454
Genome-wide analysis of estrogen receptor binding sites
Carroll, J. S., Meyer, C. A., Song, J. S., Li, W., Geistlinger, T., Eeckhoute, J., Brodsky, A. S., Keeton, E. K., Fertuck, K. C., Hall, G., et al. (2006) · Nature Genetics · doi:10.1038/ng1901 · Cited by 1,397
Cohesin mediates transcriptional insulation by CCCTC-binding factor
Wendt, K. S., Yoshida, K., Itoh, T., Bando, M., Koch, B., Schirghuber, E., Tsutsumi, S., Nagae, G., Ishihara, K., Mishiro, T., et al. (2008) · Nature · doi:10.1038/nature06634 · Cited by 1,193
A Global Map of p53 Transcription-Factor Binding Sites in the Human Genome
Wei, C.-L., Wu, Q., Vega, V. B., Chiu, K. P., Ng, P., Zhang, T., Shahab, A., Yong, H. C., Fu, Y., Weng, Z., et al. (2006) · Cell · doi:10.1016/j.cell.2005.10.043 · Cited by 1,141
Analysis of the Vertebrate Insulator Protein CTCF-Binding Sites in the Human Genome
Kim, T. H., Abdullaev, Z., Smith, A. D., Ching, K. A., Loukinov, D. I., Green, R. D., Zhang, M. Q., Lobanenkov, V. V., & Ren, B. (2007) · Cell · doi:10.1016/j.cell.2006.12.048 · Cited by 1,022
Self-citationA high-resolution map of active promoters in the human genome
Kim, T. H., Barrera, L. O., Zheng, M., Qu, C., Singer, M. A., Richmond, T., Wu, Y., Green, R. D., & Ren, B. (2005) · Nature · doi:10.1038/nature03877 · Cited by 954
Self-citationTranscriptional Regulatory Elements in the Human Genome
Maston, G. A., Evans, S. K., & Green, M. R. (2006) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.7.080505.115623 · Cited by 937 · cited 4×
“Next, we identified putative insulators in the ENCODE regions for these cell types based on CTCF binding, because mammalian insulators are generally understood to require CTCF to block promoter 2 enhancer interactions 3 .”
BackgroundInfluentialSignal Transduction and the Control of Gene Expression
Brivanlou, A. H., & Darnell, J. E. (2002) · Science · doi:10.1126/science.1066355 · Cited by 699
Feeder-independent culture of human embryonic stem cells
Ludwig, T. E., Bergendahl, V., Levenstein, M. E., Yu, J., Probasco, M. D., & Thomson, J. A. (2006) · Nature Methods · doi:10.1038/nmeth902 · Cited by 681
Self-citationDiscovery of functional elements in 12 Drosophila genomes using evolutionary signatures
Stark, A., Lin, M. F., Kheradpour, P., Pedersen, J. S., Parts, L., Carlson, J. W., Crosby, M. A., Rasmussen, M. D., Roy, S., Deoras, A. N., et al. (2007) · Nature · doi:10.1038/nature06340 · Cited by 640
Self-citationThe landscape of histone modifications across 1% of the human genome in five human cell linesPreprint
Koch, C. M., Andrews, R., Flicek, P., Dillon, S. C., Karaöz, U., Clelland, G., Wilcox, S., Beare, D. M., Fowler, J. C., Couttet, P., et al. (2007) · Genome Research · doi:10.1101/gr.5704207 · Cited by 460
Wang, Q., Carroll, J. S., & Brown, M. A. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.07.018 · Cited by 455
Promoter features related to tissue specificity as measured by Shannon entropy
Schug, J., Winfried-Paul, S., Kappen, C., Salbaum, J. M., Bućan, M., & Stoeckert, C. J. (2005) · Genome biology · doi:10.1186/gb-2005-6-4-r33 · Cited by 455
Histone modifications: signalling receptors and potential elements of a heritable epigenetic code
Nightingale, K. P., O’Neill, L. P., & Turner, B. M. (2006) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2006.02.015 · Cited by 318
Yang, A., Zhu, Z., Kapranov, P., McKeon, F., Church, G. M., Gingeras, T., & Struhl, K. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.10.018 · Cited by 285
Crawford, G. E., Davis, S. R., Scacheri, P. C., Renaud, G., Halawi, M. J., Erdos, M. R., Green, R., Meltzer, P. S., Wolfsberg, T. G., & Collins, F. S. (2006) · Nature Methods · doi:10.1038/nmeth888 · Cited by 229
Self-citationXi, H. S., Shulha, H. P., Lin, J. M., Vales, T. R., Fu, Y., Bodine, D. M., McKay, R. D. G., Chenoweth, J. G., Tesar, P. J., Furey, T. S., et al. (2005) · PLoS Genetics · doi:10.1371/journal.pgen.0030136 · Cited by 215
Self-citationKleinjan, D. A. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.19.2049 · Cited by 209
King, D. C., Taylor, J., Elnitski, L., Chiaromonte, F., Miller, W., & Hardison, R. C. (2005) · Genome Research · doi:10.1101/gr.3642605 · Cited by 208
Reliable prediction of regulator targets using 12 Drosophila genomesPreprint
Kheradpour, P., Stark, A., Roy, S., & Kellis, M. (2007) · Genome Research · doi:10.1101/gr.7090407 · Cited by 163
Self-citationModel-based analysis of two-color arrays (MA2C)
Song, J. S., Johnson, W. E., Zhu, X., Zhang, X., Li, W., Manrai, A. K., Liu, J. S., Chen, R., & Liu, X. S. (2007) · Genome biology · doi:10.1186/gb-2007-8-8-r178 · Cited by 111
Self-citationHeintzman, N. D., & Ren, B. (2006) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-006-6295-0 · Cited by 108
Self-citationWolf, A. T. (2004) · Blood · doi:10.1182/blood-2003-12-4383 · Cited by 26
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Roadmap Epigenomics Consortium, Kundaje, A., Meuleman, W., Ernst, J., Bilenky, M., Yen, A., Heravi-Moussavi, A., Kheradpour, P., Zhang, Z., Wang, J., et al. (2015) · Nature · doi:10.1038/nature14248 · Cited by 6,368
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Lister, R., Pelizzola, M., Dowen, R. H., Hawkins, R. D., Hon, G., Tonti-Filippini, J., Nery, J. R., Lee, L., Ye, Z., Ngo, Q.-M., et al. (2009) · Nature · doi:10.1038/nature08514 · Cited by 4,673
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Creyghton, M. P., Cheng, A. W., Welstead, G. G., Kooistra, T., Carey, B. W., Steine, E. J., Hanna, J., Lodato, M. A., Frampton, G. M., Sharp, P. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016071107 · Cited by 4,302
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Whyte, W. A., Orlando, D. A., Hnisz, D., Abraham, B. J., Lin, C. Y., Kagey, M. H., Rahl, P. B., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.035 · Cited by 4,143
Metadata
- Authors
- Heintzman, N. D., Hon, G. C., Hawkins, R. D., Kheradpour, P., Stark, A., Harp, L. F., Ye, Z., Lee, L. K., Stuart, R. K., Ching, C. W., Ching, K. A., Antosiewicz-Bourget, J. E., Liu, H., Zhang, X., Green, R. D., Lobanenkov, V. V., Stewart, R., Thomson, J. A., Crawford, G. E., Kellis, M., & Ren, B.
- Affiliations
- Ludwig Cancer Research (BE)
- MIT Computer Science and Artificial Intelligence Laboratory (US)
- Broad Institute (US)
- National Institute of Allergy and Infectious Diseases (US)
- Morgridge Institute for Research (US)
- University of Wisconsin–Madison (US)
- Duke University (US)
- Corresponding author
- Ren, Bing
- ORCID
- Venue
- Nature
- Published
- 2009-03-18
- Volume
- 459
- Issue
- 7243
- Pages
- 108-112
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2910248
- OpenAlex
- W2123564569
- Cited by
- 2,533
- References
- 27
- Citations by year
- 2026: 56 · 2025: 101 · 2024: 115 · 2023: 122 · 2022: 101 · 2021: 126 · 2020: 171 · 2019: 150 · 2018: 163 · 2017: 154 · 2016: 164 · 2015: 183 · 2014: 193 · 2013: 204 · 2012: 188
- FWCI
- 71.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- PubMed Central
- Funders
- National Institutes of Health
- National Human Genome Research Institute (U01HG003151, R01HG004037)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- histone modifications, enhancers, cell type-specific gene expression, promoter, insulators, CTCF binding, chromatin state, cis-regulatory elements, human cell lines, ChIP-chip
- MeSH terms
- Binding Sites, Cell Line, Cell Physiological Phenomena, Chromatin, Gene Expression Regulation, HeLa Cells, Histones, Humans, Promoter Regions, Genetic, Transcription Factors, Genome, Human, K562 Cells
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