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Repression of genes by DNA methylation depends on CpG density and promoter strength: evidence for involvement of a methyl‐CpG binding protein.
Open accessAbstract
Repression of transcription from densely methylated genes can be mediated by the methyl-CpG binding protein MeCP-1 (Boyes and Bird, 1991). Here we have investigated the effect of methylation on genes with a low density of methyl-CpG. We found that sparse methylation could repress transfected genes completely, but the inhibition was fully overcome by the presence in cis of an SV40 enhancer. Densely methylated genes, however, could not be reactivated by the enhancer. In vitro studies showed that the sparsely methylated genes bound weakly to MeCP-1 and that binding interfered with transcription. In the absence of available MeCP-1, methylation had minimal effects on transcription. From these and other results we propose that sparsely methylated genes form an unstable complex with MeCP-1 which prevents transcription when the promoter is weak. This complex can be disrupted by a strong promoter, thereby allowing the methylated gene to be transcribed.
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“DNA methylation (5-methylcytosine or 5mC) is associated with gene repression (16) and can disrupt the binding of many TFs (17, 18).”
From Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver (2019) · cites this paper as [16]
In the citing paper
“Our finding that targeted DNA methylation outside of annotated CGIs can lead to robust memorized gene silencing extends the canonical model of methylation-based gene silencing, which posits that a high density of CpG methylation is a requirement for stable propagation of silencing (Boyes and Bird, 1992).”
From Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing (2021) · cites this paper as Boyes and Bird, 1992
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“For example, Boyes and Bird (1992) found that the density of CG sites in the promoter region of a gene is associated with the stability of the inactive state: the more CG sites, the more stable the inactive state.”
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DNA Methylation-mediated Control of Sry Gene Expression in Mouse Gonadal Development*
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Susceptibility of Nonpromoter CpG Islands to De Novo Methylation in Normal and Neoplastic Cells
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“Promoters with a low density of methyl-CpGs bind MeCP-1 less strongly than those with a high density of methyl-CpGs (Boyes and Bird, 1992).”
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“The biological effects of cytosine methylation on gene expression are believed to be due to an inhibition of the binding of transcription factors (40 and references therein) or to be mediated by proteins such as MeCP1, MeCP2, and MDBP-2 which bind nonspecifically to methylated DNA (4, 5, 21, 26, 27, 40).”
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“The density of methylated cytosines has been reported to be crucial for the efficiency of repression (Boyes and Bird, 1992; Hsieh, 1994).”
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“One possible explanation for the frequently seen discrepancies described above might be the interference of transcription-initiation complexes and transcription factors with DNA methyltransferases in promoter-associated CpG islands (Meehan et al. 1989; Boyes and Bird 1992).”
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“Furthermore, while transfection or microinjection studies of in vitromethylated DNA provide a static picture of the influence of DNA methylation (6, 27, 42), the proviral template characterized here is integrated in the host genome and progressively methylated de novo.”
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“This complex is capable of repressing transcription from closely and sparsely methylated promoters, and its activity is ubiquitous in somatic cells and tissues but is notably absent in ES cells (Meehan et al., 1989; Boyes and Bird, 1991, 1992).”
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“…bind to DNA (Ben-Hattar et al., 1989), including repressor proteins Key Words: 5-azacytidine; methylation; DNA methyltransferase; notochord; somites; zebrafish. like MeCP1 and MeCP2 (methyl-cytosine binding proteins) (Boyes and Bird, 1991, 1992), or nucleosome positioning Ontario, Canada K1Y 4E9.”
Lorincz, M. C., Schübeler, D., Hutchinson, S. R., Dickerson, D. R., & Groudine, M. T. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.21.7572-7580.2002 · Cited by 125
“Transcription of an -globin reporter construct methylated at low density, for example, only occurs in the presence of an enhancer (6, 7), but even in the presence of this enhancer, dense methylation prevents transcription.”
BackgroundLucarelli, M., Fuso, A., Ström, R., & Scarpa, S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008234200 · Cited by 142
Genomic insights into cancer-associated aberrant CpG island hypermethylation
Sproul, D., & Meehan, R. R. (2013) · Briefings in Functional Genomics · doi:10.1093/bfgp/els063 · Cited by 135
“Hypermethylation of CGI promoters is tightly linked with transcriptional repression of the affected gene [23] and many promoters initially shown to be aberrantly hypermethylated in cancer correspond to known”
BackgroundWong, D. J., Foster, S. A., Galloway, D. A., & Reid, B. J. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.8.5642 · Cited by 108
“Expansion of methylation may be important for the further reduction in gene expression or for increasing the stability of methylation-mediated transcriptional repression (7, 21, 27).”
BackgroundMadi, T., Balamurugan, K., Bombardi, R. G., Duncan, G. T., & McCord, B. R. (2012) · Electrophoresis · doi:10.1002/elps.201100711 · Cited by 124
Barbot, W. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.11.2365 · Cited by 116
“Boyes and Bird (23) also showed that repression of some methylated genes can be overcome by the presence in cis of a strong enhancer.”
Thain, A., Jenkins, O. F., Clarke, A. R., & Gaston, K. (1996) · Journal of Virology · doi:10.1128/jvi.70.10.7233-7235.1996 · Cited by 103
“CpG methylation might block the binding of these transcription factors indirectly, either by changing the conformation of chromatin or by interacting with methyl-CpG-specific repressor proteins (2, 24).”
Backgroundde Mendoza, A., Nguyen, T. V., Ford, E., Poppe, D., Buckberry, S., Pflueger, J., Grimmer, M., Stolzenburg, S., Bogdanović, O., Oshlack, A., et al. (2022) · Genome biology · doi:10.1186/s13059-022-02728-5 · Cited by 130
Mammalian Methyltransferases and Methyl-CpG-Binding Domains: Proteins Involved in DNA Methylation
Hendrich, B., & Bird, A. P. (2000) · Current topics in microbiology and immunology · doi:10.1007/978-3-642-59696-4_4 · Cited by 100
Self-citationZea ribosomal repeat evolution and substitution patterns
Buckler, E. S., & Holtsford, T. P. (1996) · Molecular Biology and Evolution · doi:10.1093/oxfordjournals.molbev.a025622 · Cited by 110
“%) completely repress transcription (Boyes and Bird 1992).”
Endocrine disruption of the epigenome: a breast cancer link
Knower, K. C., To, S. Q., Leung, Y., Ho, S., & Clyne, C. D. (2014) · Endocrine Related Cancer · doi:10.1530/erc-13-0513 · Cited by 109
“…by histone modifications (Lindroth et al. 2004, Vire et al. 2006), conversely methylated CpG sites facilitate the recruitment of methyl-binding proteins to the genomic region (Boyes & Bird 1992, Bogdanovic & Veenstra 2009), which in turn recruit histone deacetylase enzymes (HDACs; Nan et al. 1998).”
BackgroundHe, R., Liu, Y., Fu, W., He, X., Liu, S., Xiao, D., & Tao, Y. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02172-y · Cited by 109
Exposing the DNA methylome iceberg
Ndlovu, ’. N., Denis, H., & Fuks, F. (2011) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2011.03.002 · Cited by 90
Role of Epigenetics in Cardiac Development and Congenital Diseases
Moore‐Morris, T., Vliet, P. P. V., Andelfinger, G., & Pucéat, M. (2018) · Physiological Reviews · doi:10.1152/physrev.00048.2017 · Cited by 133
“Methlyation of CpG-rich gene promoters is associated with repressed chromatin and reduced gene transcription (28).”
BackgroundThe Effect of DNA Methylation on Gene Regulation of Human Papillomaviruses
Rösl, F., Arab, A., Klevenz, B., & Hausen, H. Z. (1993) · Journal of General Virology · doi:10.1099/0022-1317-74-5-791 · Cited by 88
“This is in accordance with other studies (Boyes & Bird, 1992) also showing that the density of methylated CpG sites is an important parameter for the degree of repression at particular regulatory regions.”
DNA methylation: old dog, new tricks?
Spruijt, C. G., & Vermeulen, M. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2910 · Cited by 100
Epigenetic Contributions to Hormonally‐Mediated Sexual Differentiation of the Brain
McCarthy, M. M., & Nugent, B. M. (2013) · Journal of Neuroendocrinology · doi:10.1111/jne.12072 · Cited by 100
Site-selective in vivo targeting of cytosine-5 DNA methylation by zinc-finger proteins.
Carvin, C., Parr, R. D., & Kladde, M. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg853 · Cited by 94
Metadata
- Authors
- Boyes, J., & Bird, A.
- Affiliations
- Research Institute of Molecular Pathology (AT)
- Venue
- The EMBO Journal
- Published
- 1992-01-01
- Volume
- 11
- Issue
- 1
- Pages
- 327-333
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC556453
- OpenAlex
- W1821654469
- Cited by
- 471
- References
- 0
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 7 · 2023: 4 · 2022: 12 · 2021: 8 · 2020: 7 · 2019: 10 · 2018: 10 · 2017: 12 · 2016: 10 · 2015: 6 · 2014: 14 · 2013: 18 · 2012: 8
- FWCI
- 9.92
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- DNA methylation, transcriptional repression, CpG density, promoter strength, methyl-CpG binding proteins, SV40 enhancer, gene reactivation, transcriptional silencing
- MeSH terms
- Animals, Binding Sites, DNA-Binding Proteins, Gene Expression Regulation, Globins, Methylation, Models, Genetic, Promoter Regions, Genetic, Simian virus 40, Transcription, Genetic, Transfection, DNA Modification Methylases, DNA-Cytosine Methylases, Mice
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