The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase

Thomas Gerken; Christophe A Girard; Yi-Chun Loraine Tung; Celia J Webby; Vladimir Saudek; Kirsty S Hewitson; Giles S H Yeo; Michael A McDonough; Sharon Cunliffe; Luke A McNeill; Juris Galvanovskis; Patrik Rorsman; Peter Robins; Xavier Prieur; Anthony P Coll; Marcella Ma; Zorica Jovanovic; I Sadaf Farooqi; Barbara Sedgwick; Inês Barroso; Tomas Lindahl; Chris P Ponting; Frances M Ashcroft; Stephen O'Rahilly; Christopher J Schofield

doi:10.1126/science.1151710

The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase

Thomas Gerken, Christophe A Girard, Yi-Chun Loraine Tung, Celia J Webby, Vladimir Saudek, Kirsty S Hewitson, Giles S H Yeo, Michael A McDonough, Sharon Cunliffe, Luke A McNeill, Juris Galvanovskis, Patrik Rorsman, Peter Robins, Xavier Prieur, Anthony P Coll, Marcella Ma, Zorica Jovanovic, I Sadaf Farooqi, Barbara Sedgwick, Inês BarrosoTomas Lindahl, Chris P Ponting, Frances M Ashcroft, Stephen O'Rahilly, Christopher J Schofield

Deanery of Molecular, Genetic and Population Health Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1469-72
Number of pages	4
Journal	Science
Volume	318
Issue number	5855
DOIs	https://doi.org/10.1126/science.1151710
Publication status	Published - 30 Nov 2007

Keywords / Materials (for Non-textual outputs)

Amino Acid Sequence
Animals
Brain
Cell Nucleus
Computational Biology
DNA
DNA Methylation
DNA, Single-Stranded
Eating
Energy Metabolism
Fasting
Ferrous Compounds
Hypothalamus
Ketoglutaric Acids
Male
Mice
Mixed Function Oxygenases
Molecular Sequence Data
Oxo-Acid-Lyases
RNA, Messenger
Recombinant Proteins
Succinic Acid
Thymine

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10.1126/science.1151710

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Gerken, T., Girard, C. A., Tung, Y.-C. L., Webby, C. J., Saudek, V., Hewitson, K. S., Yeo, G. S. H., McDonough, M. A., Cunliffe, S., McNeill, L. A., Galvanovskis, J., Rorsman, P., Robins, P., Prieur, X., Coll, A. P., Ma, M., Jovanovic, Z., Farooqi, I. S., Sedgwick, B., ... Schofield, C. J. (2007). The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science, 318(5855), 1469-72. https://doi.org/10.1126/science.1151710

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title = "The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase",

abstract = "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.",

keywords = "Amino Acid Sequence, Animals, Brain, Cell Nucleus, Computational Biology, DNA, DNA Methylation, DNA, Single-Stranded, Eating, Energy Metabolism, Fasting, Ferrous Compounds, Hypothalamus, Ketoglutaric Acids, Male, Mice, Mixed Function Oxygenases, Molecular Sequence Data, Oxo-Acid-Lyases, RNA, Messenger, Recombinant Proteins, Succinic Acid, Thymine",

author = "Thomas Gerken and Girard, {Christophe A} and Tung, {Yi-Chun Loraine} and Webby, {Celia J} and Vladimir Saudek and Hewitson, {Kirsty S} and Yeo, {Giles S H} and McDonough, {Michael A} and Sharon Cunliffe and McNeill, {Luke A} and Juris Galvanovskis and Patrik Rorsman and Peter Robins and Xavier Prieur and Coll, {Anthony P} and Marcella Ma and Zorica Jovanovic and Farooqi, {I Sadaf} and Barbara Sedgwick and In{\^e}s Barroso and Tomas Lindahl and Ponting, {Chris P} and Ashcroft, {Frances M} and Stephen O'Rahilly and Schofield, {Christopher J}",

year = "2007",

month = nov,

day = "30",

doi = "10.1126/science.1151710",

language = "English",

volume = "318",

pages = "1469--72",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "5855",

}

Gerken, T, Girard, CA, Tung, Y-CL, Webby, CJ, Saudek, V, Hewitson, KS, Yeo, GSH, McDonough, MA, Cunliffe, S, McNeill, LA, Galvanovskis, J, Rorsman, P, Robins, P, Prieur, X, Coll, AP, Ma, M, Jovanovic, Z, Farooqi, IS, Sedgwick, B, Barroso, I, Lindahl, T, Ponting, CP, Ashcroft, FM, O'Rahilly, S & Schofield, CJ 2007, 'The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase', Science, vol. 318, no. 5855, pp. 1469-72. https://doi.org/10.1126/science.1151710

TY - JOUR

T1 - The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase

AU - Gerken, Thomas

AU - Girard, Christophe A

AU - Tung, Yi-Chun Loraine

AU - Webby, Celia J

AU - Saudek, Vladimir

AU - Hewitson, Kirsty S

AU - Yeo, Giles S H

AU - McDonough, Michael A

AU - Cunliffe, Sharon

AU - McNeill, Luke A

AU - Galvanovskis, Juris

AU - Rorsman, Patrik

AU - Robins, Peter

AU - Prieur, Xavier

AU - Coll, Anthony P

AU - Ma, Marcella

AU - Jovanovic, Zorica

AU - Farooqi, I Sadaf

AU - Sedgwick, Barbara

AU - Barroso, Inês

AU - Lindahl, Tomas

AU - Ponting, Chris P

AU - Ashcroft, Frances M

AU - O'Rahilly, Stephen

AU - Schofield, Christopher J

PY - 2007/11/30

Y1 - 2007/11/30

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Animals

KW - Brain

KW - Cell Nucleus

KW - Computational Biology

KW - DNA

KW - DNA Methylation

KW - DNA, Single-Stranded

KW - Eating

KW - Energy Metabolism

KW - Fasting

KW - Ferrous Compounds

KW - Hypothalamus

KW - Ketoglutaric Acids

KW - Male

KW - Mice

KW - Mixed Function Oxygenases

KW - Molecular Sequence Data

KW - Oxo-Acid-Lyases

KW - RNA, Messenger

KW - Recombinant Proteins

KW - Succinic Acid

KW - Thymine

U2 - 10.1126/science.1151710

DO - 10.1126/science.1151710

M3 - Article

C2 - 17991826

SN - 0036-8075

VL - 318

SP - 1469

EP - 1472

JO - Science

JF - Science

IS - 5855

ER -

The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase

Abstract

Keywords / Materials (for Non-textual outputs)

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