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Originally published in Science Express on 8 November 2007
Science 30 November 2007:
Vol. 318. no. 5855, pp. 1469 - 1472
DOI: 10.1126/science.1151710
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Reports

The Obesity-Associated FTO Gene Encodes a 2-Oxoglutarate-Dependent Nucleic Acid Demethylase

Thomas Gerken,1 Christophe A. Girard,2* Yi-Chun Loraine Tung,3* Celia J. Webby,1{dagger} Vladimir Saudek,3{dagger} Kirsty S. Hewitson,1,4{dagger} Giles S. H. Yeo,3{dagger} Michael A. McDonough,1{dagger} Sharon Cunliffe,4{dagger} Luke A. McNeill,1,4{dagger} Juris Galvanovskis,5{dagger} Patrik Rorsman,5 Peter Robins,6 Xavier Prieur,3 Anthony P. Coll,3 Marcella Ma,3 Zorica Jovanovic,3 I. Sadaf Farooqi,3 Barbara Sedgwick,6 Inês Barroso,7 Tomas Lindahl,6 Chris P. Ponting,8{ddagger}§|| Frances M. Ashcroft,2{ddagger}§|| Stephen O'Rahilly,3§|| Christopher J. Schofield1{ddagger}§||

Variants in the FTO (fat mass and obesity associated) gene are associated with increased body mass index in humans. Here, we show by bioinformatics analysis that FTO shares sequence motifs with Fe(II)- and 2-oxoglutarate–dependent oxygenases. We find that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide. Consistent with a potential role in nucleic acid demethylation, Fto localizes to the nucleus in transfected cells. Studies of wild-type mice indicate that Fto messenger RNA (mRNA) is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and that Fto mRNA levels in the arcuate nucleus are regulated by feeding and fasting. Studies can now be directed toward determining the physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass.

1 Chemistry Research Laboratory and Oxford Centre for Integrative Systems Biology, University of Oxford, 12 Mansfield Road, Oxford, Oxon OX1 3TA, UK.
2 Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, Oxon OX1 3PT, UK.
3 University of Cambridge, Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
4 ReOx Ltd., Magdalen Centre, The Oxford Science Park, Oxford, Oxon OX4 4GA, UK.
5 Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, Oxon OX3 7LJ, UK.
6 Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK.
7 Metabolic Disease Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
8 MRC Functional Genetics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, Oxon OX1 3QX, UK.

* These authors contributed equally to this work.

{dagger} These authors contributed equally to this work.

{ddagger} These authors contributed equally to this work.

§ These authors contributed equally to this work.

|| To whom correspondence should be addressed. E-mail: chris.ponting{at}dpag.ox.ac.uk (C.P.P.); frances.ashcroft{at}dpag.ox.ac.uk (F.M.A.); so104{at}medschl.cam.ac.uk (S.O.); christopher.schofield{at}chem.ox.ac.uk (C.J.S.)

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Science. ISSN 0036-8075 (print), 1095-9203 (online)