Developmentally Programmed 3′ CpG Island Methylation Confers Tissue- and Cell-Type-Specific Transcriptional Activation
Open accessAbstract
During development, a small but significant number of CpG islands (CGIs) become methylated. The timing of developmentally programmed CGI methylation and associated mechanisms of transcriptional regulation during cellular differentiation, however, remain poorly characterized. Here, we used genome-wide DNA methylation microarrays to identify epigenetic changes during human embryonic stem cell (hESC) differentiation. We discovered a group of CGIs associated with developmental genes that gain methylation after hESCs differentiate. Conversely, erasure of methylation was observed at the identified CGIs during subsequent reprogramming to induced pluripotent stem cells (iPSCs), further supporting a functional role for the CGI methylation. Both global gene expression profiling and quantitative reverse transcription-PCR (RT-PCR) validation indicated opposing effects of CGI methylation in transcriptional regulation during differentiation, with promoter CGI methylation repressing and 3' CGI methylation activating transcription. By studying diverse human tissues and mouse models, we further confirmed that developmentally programmed 3' CGI methylation confers tissue- and cell-type-specific gene activation in vivo. Importantly, luciferase reporter assays provided evidence that 3' CGI methylation regulates transcriptional activation via a CTCF-dependent enhancer-blocking mechanism. These findings expand the classic view of mammalian CGI methylation as a mechanism for transcriptional silencing and indicate a functional role for 3' CGI methylation in developmental gene regulation.
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Methylation at the 3′ end of the CpG island confers tissue-specific transcriptional activation during human embryonic stem cell differentiation.
“methylation at the 3′ end of the CpG island confers tissue-specific transcriptional activation during human ES cell differentiation100.”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [100]
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Transcription factors as readers and effectors of DNA methylation
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- Authors
- Yu, D.-H., Ware, C., Waterland, R. A., Zhang, J., Chen, M.-H., Gadkari, M., Kunde-Ramamoorthy, G., Nosavanh, L. M., & Shen, L.
- Affiliations
- Baylor College of Medicine (US)
- University of Washington (US)
- The University of Texas MD Anderson Cancer Center (US)
- Department of Pediatrics, Baylor College of Medicine, USDA/ARS Children's Nutrition Research Center
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2013-05-01
- Volume
- 33
- Issue
- 9
- Pages
- 1845-1858
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC3624169
- OpenAlex
- W1976095508
- Cited by
- 48
- References
- 82
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 4 · 2018: 3 · 2017: 8 · 2016: 3 · 2015: 5 · 2014: 4 · 2013: 6
- FWCI
- 2.69
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sidney Kimmel Foundation
- National Institutes of Health (5r01dk081557-05)
- National Institute of General Medical Sciences (P01GM081619)
- National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK081557, R01 DK081557)
- Division of Materials Research
- 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, human embryonic stem cell differentiation, induced pluripotent stem cells, reprogramming, developmental gene regulation, transcriptional activation, enhancer blocking, CTCF, tissue-specific gene expression, cell type-specific gene expression, epigenetic regulation
- MeSH terms
- CCCTC-Binding Factor, Animals, Cell Differentiation, Cell Line, DNA, Humans, Methylation, Mice, Inbred C57BL, Repressor Proteins, Transcriptional Activation, Gene Expression Regulation, Developmental, CpG Islands, DNA Methylation, Oligonucleotide Array Sequence Analysis, Epigenesis, Genetic, Mice, Embryonic Stem Cells, Induced Pluripotent Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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