DNA Demethylation in Zebrafish Involves the Coupling of a Deaminase, a Glycosylase, and Gadd45
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 mismatc...
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| Veröffentlicht in: | Cell 2008-12, Vol.135 (7), p.1201-1212 |
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| creator | Rai, Kunal Huggins, Ian J. James, Smitha R. Karpf, Adam R. Jones, David A. Cairns, Bradley R. |
| description | 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. |
| doi_str_mv | 10.1016/j.cell.2008.11.042 |
| format | Article |
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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. 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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.</description><subject>Animals</subject><subject>Cell Line</subject><subject>CELLBIO</subject><subject>Cytidine Deaminase - metabolism</subject><subject>Danio rerio</subject><subject>DEVBIO</subject><subject>DNA</subject><subject>DNA (Cytosine-5-)-Methyltransferases - metabolism</subject><subject>DNA Glycosylases - metabolism</subject><subject>DNA Methylation</subject><subject>Embryo, Nonmammalian - metabolism</subject><subject>GADD45 Proteins</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Neuropeptides - metabolism</subject><subject>Thymine DNA Glycosylase - metabolism</subject><subject>Up-Regulation</subject><subject>Zebrafish - metabolism</subject><subject>Zebrafish Proteins - metabolism</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUFv0zAYhi3ExMrgD3BAOXEi4bMTJ7aEkKaOlUnTuOzEAcuxv6yuErvEaaX-e5y1GnBhJ-uTn_eR_b2EvKNQUKD1p01hsO8LBiAKSguo2AuyoCCbvKINe0kWAJLlom6qc_I6xg0kkHP-ipxTmTAh2YL8vLq7zK5wwGl96PXkgs-cz35gO-rOxXV24_eh32PMpjVmy7Db9s4_ZKHLdErpwXkd8WMaVv3BhJgUj6O32UpbW_E35KzTfcS3p_OC3F9_vV9-y2-_r26Wl7e54RymvKsaURpqa25kbbSUdSkASiaAVU0JFISEjrYtZwKZbTnlIJqy0WATp215Qb4ctdtdO6A16KdR92o7ukGPBxW0U__eeLdWD2GvWM1kyUUSfDgJxvBrh3FSg4vzdrXHsIuqlpJVQsCzIIOZkzKB7AiaMcQ4Yvf0Ggpqrk9t1JxTc32KUpXqS6H3f__jT-TUVwI-HwFMy9w7HFU0Dr1B60Y0k7LB_c__G4Kgqmg</recordid><startdate>20081226</startdate><enddate>20081226</enddate><creator>Rai, Kunal</creator><creator>Huggins, Ian J.</creator><creator>James, Smitha R.</creator><creator>Karpf, Adam R.</creator><creator>Jones, David A.</creator><creator>Cairns, Bradley R.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20081226</creationdate><title>DNA Demethylation in Zebrafish Involves the Coupling of a Deaminase, a Glycosylase, and Gadd45</title><author>Rai, Kunal ; 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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. 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| subjects | Animals Cell Line CELLBIO Cytidine Deaminase - metabolism Danio rerio DEVBIO DNA DNA (Cytosine-5-)-Methyltransferases - metabolism DNA Glycosylases - metabolism DNA Methylation Embryo, Nonmammalian - metabolism GADD45 Proteins Humans Intracellular Signaling Peptides and Proteins - metabolism Neuropeptides - metabolism Thymine DNA Glycosylase - metabolism Up-Regulation Zebrafish - metabolism Zebrafish Proteins - metabolism |
| title | DNA Demethylation in Zebrafish Involves the Coupling of a Deaminase, a Glycosylase, and Gadd45 |
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