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FTO levels affect RNA modification and the transcriptome

A block of single-nucleotide polymorphisms within intron 1 of the FTO (fat mass and obesity associated) gene is associated with variation in body weight. Previous works suggest that increased expression of FTO, which encodes a 2-oxoglutarate-dependent nucleic acid demethylase, leads to increased bod...

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Published in:European journal of human genetics : EJHG 2013-03, Vol.21 (3), p.317-323
Main Authors: Berulava, Tea, Ziehe, Matthias, Klein-Hitpass, Ludger, Mladenov, Emil, Thomale, Jürgen, Rüther, Ulrich, Horsthemke, Bernhard
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description A block of single-nucleotide polymorphisms within intron 1 of the FTO (fat mass and obesity associated) gene is associated with variation in body weight. Previous works suggest that increased expression of FTO, which encodes a 2-oxoglutarate-dependent nucleic acid demethylase, leads to increased body weight, although the underlying mechanism has remained unclear. To elucidate the function of FTO, we examined the consequences of altered FTO levels in cultured cells and murine brain. Here we show that a knockdown of FTO in HEK293 cells affects the transcripts levels of genes involved in the response to starvation, whereas overexpression of FTO affects the transcript levels of genes related to RNA processing and metabolism. Subcellular localization of FTO further strengthens the latter notion. Using immunocytochemistry and confocal laser scanning microscopy, we detected FTO in nuclear speckles and--to a lesser and varying extent--in the nucleoplasm and nucleoli of HEK293, HeLa and MCF-7 cells. Moreover, RNA modification analyses revealed that loss of Fto affects the 3-methyluridine/uridine and pseudouridine/uridine ratios in total brain RNA. We conclude that altered levels of FTO have multiple and diverse consequences on RNA modifications and the transcriptome.
doi_str_mv 10.1038/ejhg.2012.168
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subjects a-Ketoglutaric acid
Alpha-Ketoglutarate-Dependent Dioxygenase FTO
Animals
Autophagy
Body fat
Body weight
Brain
Brain - metabolism
Cell Line
Cell Nucleus Structures - genetics
Cell Nucleus Structures - metabolism
Cloning
Confocal microscopy
Female
Gene expression
Gene Expression Regulation
Gene Knockdown Techniques
Genes
Humans
Immunocytochemistry
Introns
Localization
Male
Metabolism
Mice
Mice, Knockout
Mixed Function Oxygenases - genetics
Mixed Function Oxygenases - metabolism
Mutation
nucleic acids
Nucleoli
Obesity
Oxo-Acid-Lyases - genetics
Oxo-Acid-Lyases - metabolism
Proteins
Proteins - genetics
Proteins - metabolism
RNA modification
RNA processing
RNA Processing, Post-Transcriptional
RNA, Messenger - metabolism
Single-nucleotide polymorphism
Starvation
Transcription
Transcriptome
Uridine
Uridine - analogs & derivatives
Uridine - metabolism
title FTO levels affect RNA modification and the transcriptome
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