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DNA Demethylation in Zebrafish Involves the Coupling of a Deaminase, a Glycosylase, and Gadd45
Open accessAbstract
SUMMARY Evidence for active DNA demethylation in vertebrates is accumulating, but the mechanisms and enzymes remain unclear. Using zebrafish embryos we provide evidence for 5-methylcytosine (5-meC) removal in vivo via the coupling of a 5-meC deaminase (AID, which converts 5-meC to thymine) and a G:T mismatch-specific thymine glycosylase (Mbd4). The injection of methylated DNA into embryos induced a potent DNA demethylation activity, which was attenuated by depletion of AID or the non enzymatic factor Gadd45. Remarkably, overexpression of the deaminase/glycosylase pair AID/Mbd4 in vivo caused demethylation of the bulk genome and injected methylated DNA fragments, likely involving a G:T intermediate. Furthermore, AID or Mbd4 knockdown caused the remethylation of a set of common genes. Finally, Gadd45 promoted demethylation and enhanced functional interactions between deaminase/glycosylase pairs. Our results provide evidence for a coupled mechanism of 5-meC demethylation, whereby AID deaminates 5-meC, followed by thymine base excision by Mbd4, promoted by Gadd45.
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Cites
Stability and flexibility of epigenetic gene regulation in mammalian development
Reik, W. (2007) · Nature · doi:10.1038/nature05918 · Cited by 1,963 · cited 3×
“During mouse embryonic development, the paternal genome undergoes demethylation in a replicationindependent manner (Mayer et al., 2000; Oswald et al., 2000; Reik, 2007).”
Non-heme dioxygenases: cellular sensors and regulators jelly rolled into one?
Ozer, A., & Bruick, R. K. (2007) · Nature Chemical Biology · doi:10.1038/nchembio863 · Cited by 214
Cited by
Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1
Tahiliani, M., Koh, K. P., Shen, Y., Pastor, W. A., Bandukwala, H., Brudno, Y., Agarwal, S., Iyer, L. M., Liu, D. R., Aravind, L., et al. (2009) · Science · doi:10.1126/science.1170116 · Cited by 5,836
DNA methylation and its basic function
Moore, L. D., Le, T., & Fan, G. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2012.112 · Cited by 4,906
Linking DNA methylation and histone modification: patterns and paradigms
Cedar, H., & Bergman, Y. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2540 · Cited by 2,267
TET enzymes, TDG and the dynamics of DNA demethylation
Kohli, R. M., & Zhang, Y. (2013) · Nature · doi:10.1038/nature12750 · Cited by 1,623
Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions
Wu, H., & Zhang, Y. (2014) · Cell · doi:10.1016/j.cell.2013.12.019 · Cited by 1,065
“While some evidence suggests that Gadd45 may induce active DNA demethylation in Xenopus laevis embryos andmammalian cells (Ma et al., 2009; Rai et al., 2008; Schmitz et al., 2009), conflicting results were also reported (Jin et al.”
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Metadata
- Authors
- Rai, K., Huggins, I. J., James, S. R., Karpf, A. R., Jones, D. A., & Cairns, B. R.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-12
- Volume
- 135
- Issue
- 7
- Pages
- 1201-1212
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2111350536
- Cited by
- 657
- References
- 2
- FWCI
- 28.91
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Rai, K., Huggins, I. J., James, S. R., Karpf, A. R., Jones, D. A., & Cairns, B. R. (2008). DNA Demethylation in Zebrafish Involves the Coupling of a Deaminase, a Glycosylase, and Gadd45. Cell. https://doi.org/10.1016/j.cell.2008.11.042
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