Function of an obesity-associated gene defined
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November 13, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [1]
Oxford, UK
New research published online in the journal Science has discovered that a gene known to be associated with obesity in humans functions as a DNA modifying enzyme. The gene is called FTO. It was originally described in a mutant mouse which had a fused toe, and was later identified by genetic analyses to associate with obesity in humans. Researchers were studying the DNA sequence of this gene and found it to be highly related to genes that encode a family of enzymes called 2-oxoglutarate oxygenases (2OG). Among 2OG enzymes, it was most similar to a bacterial gene called AlkB, which functions as a DNA demethylase, meaning it removes methyl groups from DNA. The researchers purified the protein product of this gene and demonstrated that it also can function as a DNA demethylase.
DNA methylation is one of a number of "epigenetic" chromatin modifications, covalent modifications to DNA and histones that regulate gene expression. It is important for gene silencing, X-chromosomal inactivation, parental imprinting (i.e. distinguishing which gene came from mom and which from dad), and can also be a sign of DNA damage. Methylation of DNA is also thought to suppress transposable elements in our genome which can replicate themselves and re-insert into genes and lead to cancer. The study of demethylases, the enzymes which remove methyl groups, is a burgeoning field of biology, as the protein domains involved in demethylase activity are now characterized. Previously, methylation was thought to be a stable epigenetic modification, and there was great controversy as to whether methyl groups were actively removed by enzymes.
The authors found that FTO has a preference for methyl groups on thymine, which is interesting because most DNA methylation occurs on cytosine residues. Thymine methylation is known to occur in response to alkylating agents which are used for chemotherapy, so this finding would support a link between altered DNA repair and obesity, as has been suggested by other studies. Specificity might be different in vivo from what is observed in the test tube, so future studies will have follow up on this finding.
FTO is highly expressed in the hypothalamus, the region of the brain involved in energy homeostasis. Fasting was found to decrease FTO transcript levels in the arcuate nucleus of the hypothalamus, suggesting nutritional regulation of FTO levels and function. In humans, obesity is associated with gene variants in first intron of the FTO gene. Intronic mutations could affect gene transcript levels by affecting a cryptic promoter or enhancer or efficiency of gene splicing. Together, these findings suggest that altered FTO levels might predispose to obesity.
Future studies will clarify the in vivo function of this enzyme, and more generally, the importance of DNA methylation and DNA repair in obesity. This important study is sure to open new avenues of research for the obesity research field.
