News:Function of an obesity-associated gene defined

November 13, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

Oxford, UK

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.