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      N 6-Methyladenosine in Nuclear RNA is a Major Substrate of the Obesity-Associated FTO

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          Abstract

          We report here that FTO (fat mass and obesity-associated protein) exhibits efficient oxidative demethylation activity of abundant N 6-methyladenosine (m 6A) residues in RNA in vitro. FTO knockdown with siRNA led to an increased level of m 6A in mRNA, whereas overexpression of FTO resulted in a decreased level of m 6A in human cells. We further show that FTO partially colocalizes with nuclear speckles, supporting m 6A in nuclear RNA as a physiological substrate of FTO.

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

          Thomas Gerken, Christophe A J Girard, Yi-Chun Tung … (2007)
          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.
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            Inactivation of the Fto gene protects from obesity.

            Julia Fischer, Linda Koch, Christian Emmerling … (2009)
            Several independent, genome-wide association studies have identified a strong correlation between body mass index and polymorphisms in the human FTO gene. Common variants in the first intron define a risk allele predisposing to obesity, with homozygotes for the risk allele weighing approximately 3 kilograms more than homozygotes for the low risk allele. Nevertheless, the functional role of FTO in energy homeostasis remains elusive. Here we show that the loss of Fto in mice leads to postnatal growth retardation and a significant reduction in adipose tissue and lean body mass. The leanness of Fto-deficient mice develops as a consequence of increased energy expenditure and systemic sympathetic activation, despite decreased spontaneous locomotor activity and relative hyperphagia. Taken together, these experiments provide, to our knowledge, the first direct demonstration that Fto is functionally involved in energy homeostasis by the control of energy expenditure.
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              Methylated nucleotides block 5' terminus of HeLa cell messenger RNA.

              C. Wei, A Gershowitz, B. Moss (1975)
              Polyadenylylated [poly(A)+] mRNA from HeLa cells that were labeled with [3H-methyl]-methionine and 14C-uridine was isolated by poly(U)-Sepharose chromatography. The presence of approximately two methyl groups per 1000 nucleotides of poly(A)+ RNA was calculated from the 3H/14C ratios and known degrees of methylation of 18S and 28S ribosomal RNAs. All four 2'-O-methylribonucleosides, but only two base-methylated derivatives, 7-methylguanosine (7MeG) and 6-methyladenosine (6MeA), were identified. 6MeA was the major component accounting for approximately 50% of the total methyl-labeled ribonucleosides. 7MeG, comprising about 10% of the total, was present exclusively at the 5' terminus of the poly(A)+ RNA and could be removed by periodate oxidation and beta elimination. Evidence for a 5' to 5' linkage of 7MeG to adjacent 2'-O-methylribonucleosides through at least two and probably three phosphates to give structures of the type 7MeG5'ppp5pNMep- and 7MeG5'ppp5'NMepNmep- was presented. The previous finding of similar sequences of methylated nucleotides in mRNA synthesized in vitro by enzymes associated with virus cores indicates that blocked 5' termini may be a characteristic feature of mRNAs that function in eucaryotic cells.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101231976
                Journal ID (pubmed-jr-id): 32624
                Journal ID (nlm-ta): Nat Chem Biol
                Journal ID (iso-abbrev): Nat. Chem. Biol.
                Title: Nature Chemical Biology
                ISSN (Print): 1552-4450
                ISSN (Electronic): 1552-4469
                Publication date Nihms-submitted: 5 August 2011
                Publication date (Electronic): 16 October 2011
                Publication date PMC-release: 1 June 2012
                Volume: 7
                Issue: 12
                Pages: 885-887
                Affiliations
                [1 ]Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA
                [2 ]Genome Structure and Stability Group, Disease Genomics and Personalized Medicine Laboratory, Beijing Institute of Genomics, Chinese Academy of Sciences, No.7 Beitucheng West Road, Chaoyang District, Beijing 100029, PR China
                [3 ]Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, 929 East 57 th Street, Chicago, Illinois 60637, USA
                [4 ]Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, UK
                Author notes
                [★ ]Correspondence and requests for materials should be addressed to C.H. chuanhe@ 123456uchicago.edu
                [5]

                These authors contributed equally to this work.

                Article
                Manuscript ID: nihpa316493
                DOI: 10.1038/nchembio.687
                PMC ID: 3218240
                PubMed ID: 22002720
                SO-VID: d9ec3e52-a066-40e5-b226-5d0eb557426c
                License:

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: R01 GM071440-07 || GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: R01 GM071440-06 || GM
                Categories
                Subject: Article

                ScienceOpen disciplines: Biochemistry
                Data availability:
                ScienceOpen disciplines: Biochemistry

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