PUBLICATION
DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45
- Authors
- Rai, K., Huggins, I.J., James, S.R., Karpf, A.R., Jones, D.A., and Cairns, B.R.
- ID
- ZDB-PUB-090106-28
- Date
- 2008
- Source
- Cell 135(7): 1201-1212 (Journal)
- Registered Authors
- Keywords
- DEVBIO, CELLBIO, DNA
- MeSH Terms
-
- Animals
- Cell Line
- Cytidine Deaminase/metabolism
- DNA (Cytosine-5-)-Methyltransferases/metabolism*
- DNA Glycosylases/metabolism*
- DNA Methylation*
- Embryo, Nonmammalian/metabolism
- Humans
- Intracellular Signaling Peptides and Proteins/metabolism*
- Neuropeptides/metabolism
- Thymine DNA Glycosylase/metabolism*
- Up-Regulation
- Zebrafish/metabolism*
- Zebrafish Proteins/metabolism*
- PubMed
- 19109892 Full text @ Cell
Citation
Rai, K., Huggins, I.J., James, S.R., Karpf, A.R., Jones, D.A., and Cairns, B.R. (2008) DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45. Cell. 135(7):1201-1212.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping