DNA methylation represses transcription in vivo
Abstract
DNA in somatic tissue is characterized by a bimodal pattern of methylation, which is established in the animal through a series of developmental events. In the mouse blastula, most DNA is unmethylated, but after implantation a wave of de novo methylation modifies most of the genome, excluding the majority of CpG islands, which are mainly associated with housekeeping genes. This genomic methylation pattern is broadly maintained during the life of the organism by maintenance methylation, and generally correlates with gene expression. Experiments both in vitro and in vivo indicate that methylation inhibits transcription. It has not yet been possible, however, to determine the role of DNA methylation on specific sequences during normal development. Cis-acting regulatory elements and trans-acting factors appear to be involved in both stage- and tissue-specific demethylation processes. Sp1-like elements have a key role in protecting the CpG island of Aprt (encoding adenine phosphoribosyltransferase) from de novo methylation, and when these elements are specifically mutated, the Aprt CpG island becomes methylated in transgenic mice. We have now characterized an embryo-specific element from the CpG island sequence upstream of Aprt that can protect itself from de novo methylation in transgenic mice as well as reduce methylation of flanking sequences. We placed this element on a removable cassette adjacent to a human HBB (encoding beta-globin) reporter and generated a transgene whose methylation pattern can be switched in vivo. Analysis of globin transcription in this system showed that methylation in cis inhibits gene expression in a variety of tissues, indicating that DNA modification may serve as a global genomic repressor.
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The location of CGIs determines the direction of this regulation.
“and that the location of these CGIs determines the direction of this regulation [6, 43, 45, 55]”
Promoter CGI hypermethylation represses transcription, whereas hypermethylation at gene body CGIs activates gene expression.
“It is well-known that promoter CGI hypermethylation represses transcription [43, 45], whereas hypermethylation at gene body CGIs activates gene expression [6, 55].”
The level of methylation in CGIs regulates gene expression.
“it is widely accepted that the level of methylation in the regions known as CGI regulates gene expression”
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- Authors
- Siegfried, Z., Eden, S., Mendelsohn, M., Feng, X., Tsuberi, B.-Z., & Cedar, H.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Cedar, Howard
- Venue
- Nature Genetics
- Published
- 1999-06
- Volume
- 22
- Issue
- 2
- Pages
- 203-206
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- DOI
- 10.1038/9727
- OpenAlex
- W1554534316
- Cited by
- 354
- References
- 31
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 8 · 2023: 12 · 2022: 12 · 2021: 13 · 2020: 7 · 2019: 5 · 2018: 8 · 2017: 11 · 2016: 10 · 2015: 16 · 2014: 17 · 2013: 10 · 2012: 12
- FWCI
- 7.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- DNA methylation, transcriptional repression, de novo methylation, maintenance methylation, CpG islands, adenine phosphoribosyltransferase, embryonic development, beta-globin, cis-regulatory elements, trans-acting factors, demethylation, gene expression regulation
- MeSH terms
- Adenine Phosphoribosyltransferase, Animals, Base Sequence, Embryo, Mammalian, Globins, Humans, Mice, Transgenic, Molecular Sequence Data, Transcription, Genetic, Restriction Mapping, Dinucleoside Phosphates, Mutagenesis, Insertional, Genes, Reporter, Gene Expression Regulation, Developmental, DNA Methylation, Reverse Transcriptase Polymerase Chain Reaction, Mice
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