High-throughput engineering of a mammalian genome reveals building principles of methylation states at CG rich regions
Open accessAbstract
The majority of mammalian promoters are CpG islands; regions of high CG density that require protection from DNA methylation to be functional. Importantly, how sequence architecture mediates this unmethylated state remains unclear. To address this question in a comprehensive manner, we developed a method to interrogate methylation states of hundreds of sequence variants inserted at the same genomic site in mouse embryonic stem cells. Using this assay, we were able to quantify the contribution of various sequence motifs towards the resulting DNA methylation state. Modeling of this comprehensive dataset revealed that CG density alone is a minor determinant of their unmethylated state. Instead, these data argue for a principal role for transcription factor binding sites, a prediction confirmed by testing synthetic mutant libraries. Taken together, these findings establish the hierarchy between the two cis-encoded mechanisms that define the DNA methylation state and thus the transcriptional competence of CpG islands.
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CpG density shows a negative correlation with methylation level.
“They found that CpG density showed a negative correlation with methylation level”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [83]
Altering the sequences of binding motifs decreases overall methylation levels.
“when the sequences of binding motifs were altered, overall methylation levels decreased83.”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [83]
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- Authors
- Krebs, A. R., Dessus-Babus, S., Burger, L., & Schübeler, D.
- Affiliations
- Friedrich Miescher Institute (CH)
- SIB Swiss Institute of Bioinformatics (CH)
- University of Basel (CH)
- Corresponding author
- Schübeler, Dirk
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2014-09-26
- Volume
- 3
- Pages
- e04094-e04094
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC4381937
- OpenAlex
- W2150627055
- Cited by
- 81
- References
- 43
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 8 · 2023: 1 · 2022: 8 · 2021: 9 · 2020: 11 · 2019: 9 · 2018: 7 · 2017: 6 · 2016: 7 · 2015: 10 · 2014: 1
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- EMBO (Long Term Fellowship)
- Novartis
- European Union (NoE ‘EpiGeneSys’ FP7-HEALTH-2010-257082, ‘CADMAD’ FP7-ICT-265505, ‘Blueprint’; FP7-282510)
- European Research Council (EpiGePlas)
- Swiss Initiative in Systems Biology (SystemsX.ch) (RTD Cell Plasticity)
- Swiss National Science Foundation (Sinergia Program)
- 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, CpG islands, promoter methylation, transcription factor binding sites, cis-regulatory elements, sequence motifs, mouse embryonic stem cells, high-throughput mutagenesis, transcriptional competence
- MeSH terms
- Animals, Base Sequence, Cell Differentiation, Genetic Engineering, Humans, Mammals, Models, Genetic, Protein Binding, Transcription Factors, Gene Library, Genome, CpG Islands, DNA Methylation, Recombinases, Mice, Embryonic Stem Cells, High-Throughput Nucleotide Sequencing
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