FTO gene

3LFM, 4IDZ, 4IE0, 4IE4, 4IE5, 4IE6, 4IE7, 4CXW, 4CXX, 4CXY, 4QHO, 4QKN, 4ZS3, 4ZS27906826383ENSG00000140718ENSMUSG00000055932Q9C0B1Q8BGW1NM_001080432NM_011936NP_001350827NP_001350828NP_001350829NP_001350830NP_001350832NP_001350834NP_001350917NP_036066Fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase FTO is an enzyme that in humans is encoded by the FTO gene located on chromosome 16. As one homolog in the AlkB family proteins, it is the first mRNA demethylase that has been identified. Certain variants of the FTO gene appear to be correlated with obesity in humans. Fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase FTO is an enzyme that in humans is encoded by the FTO gene located on chromosome 16. As one homolog in the AlkB family proteins, it is the first mRNA demethylase that has been identified. Certain variants of the FTO gene appear to be correlated with obesity in humans. The amino acid sequence of the transcribed FTO protein shows high similarity with the enzyme AlkB which oxidatively demethylates DNA. FTO is a member of the superfamily of alpha-ketoglutarate-dependent hydroxylase, which are non-heme iron-containing proteins. Recombinant FTO protein was first discovered to catalyze demethylation of 3-methylthymine in single-stranded DNA, and 3-methyluridine in single-stranded RNA, with low efficiency. The nucleoside N6-methyladenosine, an abundant modification in RNA, was then found to be a major substrate of FTO. The FTO gene expression was also found to be significantly upregulated in the hypothalamus of rats after food deprivation and strongly negatively correlated with the expression of orexigenic galanin-like peptide which is involved in the stimulation of food intake. Increases in hypothalamic expression of FTO are associated with the regulation of energy intake but not feeding reward. People with two copies of the risk allele for the rs9939609 single nucleotide polymorphism (SNP) showed differing neural responses to food images via fMRI. However, rs9939609's association with FTO is controversial, and may actually affect another gene, called iroquious homeobox protein 3 (IRX3). N6-methyladenosine (m6A) is an abundant modification in mRNA and is found within some viruses, and most eukaryotes including mammals, insects, plants, and yeast. It is also found in tRNA, rRNA, and small nuclear RNA (snRNA) as well as several long non-coding RNA, such as Xist. Adenosine methylation is directed by a large m6A methyltransferase complex containing METTL3 as the SAM-binding sub-unit. In vitro, this methyltransferase complex preferentially methylates RNA oligonucleotides containing GGACU and a similar preference was identified in vivo in mapped m6A sites in Rous sarcoma virus genomic RNA and in bovine prolactin mRNA. In plants, the majority of the m6A is found within 150 nucleotides before the start of the poly(A) tail. Mapping of m6A in human and mouse RNA has identified over 18,000 m6A sites in the transcripts of more than 7,000 human genes with a consensus sequence of m6AC consistent with the previously identified motif. Sites preferentially appear in two distinct landmarks—around stop codons and within long internal exons—and are highly conserved between human and mouse. A subset of stimulus-dependent, dynamically modulated sites has been identified. Silencing the m6A methyltransferase significantly affects gene expression and alternative RNA splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis. FTO has been demonstrated to efficiently demethylate the related modified ribonucleotide, N6,2'-O-dimethyladenosine, and to an equal or lesser extent, m6A, in vitro . FTO knockdown with siRNA led to increased amounts of m6A in polyA-RNA, whereas overexpression of FTO resulted in decreased amounts of m6A in human cells. FTO partially co-localizes with nuclear speckles, which supports the notion that in the nucleus, m6A can be a substrate of FTO. Function of FTO could affect the processing of pre-mRNA, other nuclear RNAs, or both. The discovery of the FTO-mediated oxidative demethylation of RNA may initiate further investigations on biological regulation based on reversible chemical modification of RNA, and identification of RNA substrates for which FTO has the highest affinity. FTO can oxidize m6A to generate N6 -hydroxymethyladenosine(hm6A) as an intermediate modification and N6 - formyladenosine(f6A) as a further oxidized product in mammalian cells. The FTO gene is widely expressed in both fetal and adult tissues.