FTO levels affect RNA modification and the transcriptome
FTO levels affect RNA modification and the transcriptome
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DOI：
10.1038/ejhg.2012.168
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发表时间：
2013-03-01
影响因子：
5.2
通讯作者：
Horsthemke, Bernhard
中科院分区：
文献类型：
--
作者：
Berulava, Tea;Ziehe, Matthias;Horsthemke, Bernhard
FTO（脂肪量和肥胖相关）基因内含子1内的单核苷酸多态性与体重变化相关。先前的工作表明，FTO（编码2-酮戊二酸依赖性核酸脱甲基酶）表达的增加导致体重增加，尽管其潜在机制仍不清楚。为了阐明FTO的功能，我们研究了培养细胞和小鼠脑中FTO水平改变的后果。在这里，我们表明HEK 293细胞中FTO的敲低会影响参与饥饿反应的基因的转录水平，而FTO的过表达会影响与RNA加工和代谢相关的基因的转录水平。FTO的亚细胞定位进一步加强了后者的概念。使用免疫细胞化学和共聚焦激光扫描显微镜，我们检测到FTO核斑点和-在较小的和不同程度的-在HEK 293，HeLa和MCF-7细胞的核质和核仁。此外，RNA修饰分析表明，Fto的损失影响总脑RNA中的3-甲基尿苷/尿苷和假尿苷/尿苷比率。我们的结论是，FTO水平的改变对RNA修饰和转录组具有多种多样的后果。欧洲人类遗传学杂志（2013）21，317-323; doi：10.1038/ejhg.2012.168; 2012年8月8日在线发表
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. European Journal of Human Genetics (2013) 21, 317-323; doi:10.1038/ejhg.2012.168; published online 8 August 2012