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Changes in gene expression associated with FTO overexpression in mice.

ABSTRACT: Single nucleotide polymorphisms in the first intron of the fat-mass-and-obesity-related gene FTO are associated with increased body weight and adiposity. Increased expression of FTO is likely underlying this obesity phenotype, as mice with two additional copies of Fto (FTO-4 mice) exhibit increased adiposity and are hyperphagic. FTO is a demethylase of single stranded DNA and RNA, and one of its targets is the m6A modification in RNA, which might play a role in the regulation of gene expression. In this study, we aimed to examine the changes in gene expression that occur in FTO-4 mice in order to gain more insight into the underlying mechanisms by which FTO influences body weight and adiposity. Our results indicate an upregulation of anabolic pathways and a downregulation of catabolic pathways in FTO-4 mice. Interestingly, although genes involved in methylation were differentially regulated in skeletal muscle of FTO-4 mice, no effect of FTO overexpression on m6A methylation of total mRNA was detected.

SUBMITTER: Merkestein M

PROVIDER: S-EPMC4026227 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Changes in gene expression associated with FTO overexpression in mice.

Merkestein Myrte M McTaggart James S JS Lee Sheena S Kramer Holger B HB McMurray Fiona F Lafond Mathilde M Boutens Lily L Cox Roger R Ashcroft Frances M FM

PloS one 20140519 5

Single nucleotide polymorphisms in the first intron of the fat-mass-and-obesity-related gene FTO are associated with increased body weight and adiposity. Increased expression of FTO is likely underlying this obesity phenotype, as mice with two additional copies of Fto (FTO-4 mice) exhibit increased adiposity and are hyperphagic. FTO is a demethylase of single stranded DNA and RNA, and one of its targets is the m6A modification in RNA, which might play a role in the regulation of gene expression. ...[more]

PMID: 24842286

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Project description:BackgroundThe kidney is a major organ in which fluid balance and waste excretion is regulated. For the kidney to achieve maturity with functions, normal renal developmental processes need to occur. Comprehensive genetic programs underlying renal development during the prenatal period have been widely studied. However, postnatal renal development, from infancy to the juvenile period, has not been studied yet. Here, we investigated whether structural and functional kidney development was still ongoing in early life by analyzing the renal transcriptional networks of infant (4 weeks old) and juvenile (7 weeks old) mice. We further examined the effects of dehydration on kidney development to unravel the mechanistic bases underlying deteriorative impact of pediatric dehydration on renal development.Methods3-week-old infant mice that just finished weaning period were provided limited access to a water for fifteen minutes per day for one week (RES 1W) and four weeks (RES 4W) to induce dehydration while control group consumed water ad libitum with free access to the water bottle. Transcriptome analysis was conducted to understand physiological changes during postnatal renal development and dehydration.ResultsKidneys in 4-week- and 7-week-old mice showed significantly distinctive functional gene networks. Gene sets related to cell cycle regulators, fetal kidney patterning molecules, and immature basement membrane integrity were upregulated in infantile kidneys while heightened expressions of genes associated with ion transport and drug metabolism were observed in juvenile kidneys. Dehydration during infancy suppressed renal growth by interrupting the SHH signaling pathway, which targets cell cycle regulators. Importantly, it is likely that disruption of the developmental program ultimately led to a decline in gene expression associated with basement membrane integrity.ConclusionsAltogether, we demonstrate transcriptional events during renal development in infancy and show that the impacts of inadequate water intake in the early postnatal state heavily rely on the impairment of normal renal development. Here, we provide a meaningful perspective of renal development in infancy with a molecular and physiological explanation of why infants are more vulnerable to dehydration than adults. These results provide new insights into the molecular effects of dehydration on renal physiology and indicate that optimal nutritional interventions are necessary for pediatric renal development.

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Changes in gene expression associated with FTO overexpression in mice.

Publications

Changes in gene expression associated with FTO overexpression in mice.

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