A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters
Open accessAbstract
A striking feature of the human genome is the dearth of CpG dinucleotides (CpGs) interrupted occasionally by CpG islands (CGIs), regions with relatively high content of the dinucleotide. CGIs are generally associated with promoters; genes, whose promoters are especially rich in CpG sequences, tend to be expressed in most tissues. However, all working definitions of what constitutes a CGI rely on ad hoc thresholds. Here we adopt a direct and comprehensive survey to identify the locations of all CpGs in the human genome and find that promoters segregate naturally into two classes by CpG content. Seventy-two percent of promoters belong to the class with high CpG content (HCG), and 28% are in the class whose CpG content is characteristic of the overall genome (low CpG content). The enrichment of CpGs in the HCG class is symmetric and peaks around the core promoter. The broad-based expression of the HCG promoters is not a consequence of a correlation with CpG content because within the HCG class the breadth of expression is independent of the CpG content. The overall depletion of CpGs throughout the genome is thought to be a consequence of the methylation of some germ-line CpGs and their susceptibility to mutation. A comparison of the frequencies of inferred deamination mutations at CpG and GpC dinucleotides in the two classes of promoters using SNPs in human-chimpanzee sequence alignments shows that CpGs mutate at a lower frequency in the HCG promoters, suggesting that CpGs in the HCG class are hypomethylated in the germ line.
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Two-thirds of human genes have CGIs within their promoters.
“Two-thirds of human genes have CGIs within their promoters35”
From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [35]
The Abstract (page unavailable) reports that 72% of human promoters have high CpG content, broadly consistent with the claimed proportion. But the paper deliberately avoids defining CpG islands by a threshold, so it does not establish that two-thirds of genes have CGIs within their promoters. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHuman promoters are mostly CG-rich and have distinct promoter architecture and regulation compared to CG-poor promoters which are mostly tissue-specific.
“Human promoters are mostly CG-rich35,62 and have distinct promoter architecture and regulation11 compared to CG-poor promoters which are mostly tissue-specific17”
From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [35]
The Results (Fig. 1) classify 72% of human promoters as high-CpG and describe a different CpG pattern around the transcription start site in the two classes. The Results (Fig. 3) find that expression in only a few tissues is more common in the low-CpG class, but do not establish that most low-CpG promoters are tissue-specific. The Discussion says evidence about methylation-mediated regulation of low-CpG promoters is limited, so distinct regulation is not established here. (LLM, conf=0.88)
Experimental — accuracy not yet measured
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Percentages, sums and reported differences re-computed from the paper’s own numbers.
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- Authors
- Saxonov, S., Berg, P., & Brutlag, D. L.
- Affiliations
- Stanford University (US)
- ORCID
- Berg, Paul
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-01-23
- Volume
- 103
- Issue
- 5
- Pages
- 1412-1417
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1345710
- OpenAlex
- W2137505881
- Cited by
- 1,401
- References
- 4
- Citations by year
- 2026: 48 · 2025: 58 · 2024: 76 · 2023: 58 · 2022: 68 · 2021: 83 · 2020: 71 · 2019: 72 · 2018: 83 · 2017: 76 · 2016: 63 · 2015: 87 · 2014: 63 · 2013: 110 · 2012: 85
- FWCI
- 17.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Profiles in Science (submittedVersion)
- Funders
- U.S. National Library of Medicine
- 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 › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- CpG, CpG islands, promoter classification, human genome, CpG methylation, core promoter, gene expression breadth, CpG content
- MeSH terms
- Animals, Pan troglodytes, Exons, Humans, Introns, Models, Genetic, Mutation, Nucleotides, Promoter Regions, Genetic, Genome, Human, Sequence Analysis, DNA, Germ-Line Mutation, CpG Islands, DNA Methylation, Oligonucleotide Array Sequence Analysis, Epigenesis, Genetic
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