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The Obesity-Associated FTO Gene Encodes a 2-Oxoglutarate-Dependent Nucleic Acid Demethylase
Thomas Gerken,1Christophe A. Girard,2*Yi-Chun Loraine Tung,3*Celia J. Webby,1Vladimir Saudek,3Kirsty S. Hewitson,1,4Giles S. H. Yeo,3Michael A. McDonough,1Sharon Cunliffe,4Luke A. McNeill,1,4Juris Galvanovskis,5Patrik Rorsman,5Peter Robins,6Xavier Prieur,3Anthony P. Coll,3Marcella Ma,3Zorica Jovanovic,3I. Sadaf Farooqi,3Barbara Sedgwick,6Inês Barroso,7Tomas Lindahl,6Chris P. Ponting,8||Frances M. Ashcroft,2||Stephen O'Rahilly,3||Christopher J. Schofield1||
Variants in the FTO (fat mass and obesity associated) gene areassociated with increased body mass index in humans. Here, weshow by bioinformatics analysis that FTO shares sequence motifswith Fe(II)- and 2-oxoglutarate–dependent oxygenases.We find that recombinant murine Fto catalyzes the Fe(II)- and2OG-dependent demethylation of 3-methylthymine in single-strandedDNA, with concomitant production of succinate, formaldehyde,and carbon dioxide. Consistent with a potential role in nucleicacid demethylation, Fto localizes to the nucleus in transfectedcells. Studies of wild-type mice indicate that Fto messengerRNA (mRNA) is most abundant in the brain, particularly in hypothalamicnuclei governing energy balance, and that Fto mRNA levels inthe arcuate nucleus are regulated by feeding and fasting. Studiescan now be directed toward determining the physiologically relevantFTO substrate and how nucleic acid methylation status is linkedto 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.
These authors contributed equally to this work.
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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These authors contributed equally to this work. 
These authors contributed equally to this work. 
These authors contributed equally to this work. 
