Studies have revealed an association between variants of the first intron of the human FTO gene and obesity. Computational analyses predict that the protein product of FTO contains a 2-oxoglutarate oxygenase (2OG) fold, and these enzymes have been found to be involved in diverse cellular processes, ranging from DNA repair to histone demethylation. Here, authors characterized a recombinant form of FTO to determine if this protein is a 2OG enzyme. To this end, they expressed a His- tagged form of FTO in E.coli, and assays specific to 2OG oxygenases showed that Fto catalyzed 2OG decarboxylation, activity which was in turn stopped by 2OG oxygenase- specific inhibitors. As the sequence of FTO resembled that of AlkB, an DNA repair oxygenase from E.coli related to methylation lesions, Gerken et al., screened for known AlkB targets and other common substrates of 2OG oxygenases (for example, me-H3K9), and found that only 1-methyl adenine "stimulated turnover of 2OG above control levels." Mass spectrometry coupled with liquid chromatography revealed that Fto catalyzed Fe++ and 2OG- dependent DNA demethylation. Fto was active also in single- stranded DNA, and YFP-Fto transfected to cell lines were located mostly at nuclei, as expected for any DNA demethylase. With many links already found between DNA methylation modifications and nutrition, it still remains to see if there is an actual causal relationship between obesity and epigenetics.
Gerken T., et al. 2007. Science 318(5855):1469-1472
epigenetics
