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

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]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[2]  R. Dildrop,et al.  The mouse Fused toes (Ft) mutation is the result of a 1.6-Mb deletion including the entire Iroquois B gene cluster , 2002, Mammalian Genome.

[3]  M. Jarvelin,et al.  A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity , 2007, Science.

[4]  David G. Watson,et al.  Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. , 2005, Cancer cell.

[5]  E. Seeberg,et al.  AlkB restores the biological function of mRNA and tRNA inactivated by chemical methylation. , 2004, Molecular cell.

[6]  S. O’Rahilly,et al.  Monogenic obesity in humans. , 2005, Annual review of medicine.

[7]  Thomas L. Madden,et al.  Improving the accuracy of PSI-BLAST protein database searches with composition-based statistics and other refinements. , 2001, Nucleic acids research.

[8]  Eugene V Koonin,et al.  The DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate- and iron-dependent dioxygenases , 2001, Genome Biology.

[9]  Robert P. Hausinger,et al.  Fe(II)/α-Ketoglutarate-Dependent Hydroxylases and Related Enzymes , 2004 .

[10]  Beverley Balkau,et al.  Variation in FTO contributes to childhood obesity and severe adult obesity , 2007, Nature Genetics.

[11]  Michael I. Wilson,et al.  Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation , 2001, Science.

[12]  G. Abecasis,et al.  A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants , 2007, Science.

[13]  T. Lindahl,et al.  Demethylation of 3-Methylthymine in DNA by Bacterial and Human DNA Dioxygenases* , 2004, Journal of Biological Chemistry.

[14]  C. Corless,et al.  The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Pingfang Liu,et al.  Genomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6 , 2006, Cell.

[16]  James Strait,et al.  Genome-Wide Association Scan Shows Genetic Variants in the FTO Gene Are Associated with Obesity-Related Traits , 2007, PLoS genetics.

[17]  J. Hoeijmakers,et al.  Impaired Genome Maintenance Suppresses the Growth Hormone–Insulin-Like Growth Factor 1 Axis in Mice with Cockayne Syndrome , 2006, PLoS biology.

[18]  Robert P. Hausinger,et al.  Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage , 2002, Nature.

[19]  C. Mantzoros,et al.  Role of leptin in the neuroendocrine response to fasting , 1996, Nature.

[20]  P. Bates,et al.  Reversal of DNA alkylation damage by two human dioxygenases , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[21]  A. Bjørk,et al.  Repair deficient mice reveal mABH2 as the primary oxidative demethylase for repairing 1meA and 3meC lesions in DNA , 2006, The EMBO journal.

[22]  G. Pfeifer,et al.  Repair of Methylation Damage in DNA and RNA by Mammalian AlkB Homologues* , 2005, Journal of Biological Chemistry.

[23]  김삼묘,et al.  “Bioinformatics” 특집을 내면서 , 2000 .

[24]  M. D. Lloyd,et al.  Structure of a cephalosporin synthase , 1998, Nature.

[25]  J. Tainer,et al.  Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage , 2006, The EMBO journal.

[26]  A. Chadli.  THE CANCER CELL , 1924, La Presse medicale.

[27]  Paul Tempst,et al.  The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36 , 2006, Nature.

[28]  宁北芳,et al.  疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A , 2005 .

[29]  M. Ivan,et al.  HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing , 2001, Science.

[30]  J. Essigmann,et al.  Mutagenesis, genotoxicity, and repair of 1-methyladenine, 3-alkylcytosines, 1-methylguanine, and 3-methylthymine in alkB Escherichia coli. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Magnar Bjørås,et al.  Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA , 2003, Nature.

[32]  R. Rosenfeld.  Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[33]  C. Schofield,et al.  Structural studies on 2-oxoglutarate oxygenases and related double-stranded beta-helix fold proteins. , 2006, Journal of inorganic biochemistry.