美国犹他州大学肿瘤科学系，药物化学系，霍华休斯医学院，Huntsman癌症研究所以及Roswell Park癌症研究所药理与治疗学系的研究者在DNA去甲基化的研究上取得新的进展，相关成果公布在最新一期（12月26日）的Cell上。
脊椎动物的DNA去甲基化问题一直以来都备受关注，尽管到目前为止相关的研究理论已经积累了不少，但是去甲基化的准确机制或是参与其中的酶这两个方面的研究一直没有取得突破性的进展。以斑马鱼胚胎为研究对象，Bradley研究人员取得了新的进展，研究结果表明，细胞内去除5-methylcytosine（5-meC）必须要有5-meC deaminase（简称AIDS，5-meC脱氨基酶，可将5-meC转化为胸腺嘧啶）与G:T mismatch-specific thymine glycosylase（Mbd4）同时发挥作用。如果在胚胎中注射一些甲基化的DNA会诱导细胞产生去甲基化活性，如果细胞缺失AID或是缺失酶因子Gadd45则去甲基化的活性将被削弱。
值得关注的是，活细胞中过度表达AID或是Mbd4会引起基因组大面积的发生去甲基化。此外，敲除AID或是Mbd4会导致普通基因产生再次的甲基化作用。最终，Gadd45具有促进去甲基化以及增强AID与Mbd4间的相互作用的功能。
研究成果最终表明，5-meC去甲基化是由一个双因子控制机制控制的，首先AID去氨基化，接下来胸腺嘧啶的碱基被Mbd4切除，这一过程由Gadd45因子其促进作用。（生物谷Bioon.com）
生物谷推荐原始出处：
Cell,26 December 2008 doi:10.1016/j.cell.2008.11.042
DNA Demethylation in Zebrafish Involves the Coupling of a Deaminase, a Glycosylase, and Gadd45
Kunal Rai1,3,4,Ian J. Huggins4,Smitha R. James5,Adam R. Karpf5,David A. Jones1,2,4,,andBradley R. Cairns1,3,4,,
1 Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA
2 Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA
3 Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT 84112, USA
4 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
5 Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
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 invivo 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 thedeaminase/glycosylase pair AID/Mbd4 invivo 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.
