FTO demethylase activity is essential for normal bone growth and bone mineralization in mice

Sachse, G.; Church, Chris; Stewart, Michelle; Cater, Heather; Teboul, Lydia; Cox, Roger D.; Ashcroft, Frances M.

doi:10.1016/j.bbadis.2017.11.027

Cited by 25 publications

(24 citation statements)

References 39 publications

(66 reference statements)

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“…Fibroblasts carrying the mutation showed impaired cell proliferation and accelerated cell senescence during culture. Developmental phenotypes of a mouse model carrying human R316Q are similar not only to the mutation‐carrying infants but also to other Fto ‐deficient mouse models, including lower body weight and lean body mass in terms of developmental aspects.…”

Section: Discussionmentioning

confidence: 71%

The Fat Mass‐ and Obesity‐Associated (FTO) Gene to Obesity: Lessons from Mouse Models

Chang

Park

et al. 2018

Obesity

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Objective Genetic variants at the fat mass‐ and obesity‐associated (FTO) locus are strongly associated with obesity‐related traits by regulating neighboring genes. Nevertheless, it is possible that FTO protein is directly involved in mechanisms regulating body composition and adiposity. Here, the in vivo biological functions of FTO in the risk for obesity were studied by reviewing murine models. Methods The effects of the locus‐specific manipulations of the murine Fto gene on metabolic‐related phenotypes in genetically modified mouse models were reviewed and summarized into the following three categories: growth and body composition, eating behaviors, and metabolic homeostasis. Results The mouse models showed different phenotypes depending on target tissues and methods for gene manipulation. Mice harboring deletions or point mutations at the Fto locus had high metabolic rates, while FTO‐overexpressing mice showed dyslipidemia. Both deletion and overexpression of the Fto gene led to abnormal eating behaviors. Intriguingly, several phenotypes were differently expressed depending on developmental timing of the genetic manipulations. For instance, a germ line deletion decreased total body fat mass, while the deletion in adult mice increased it. Conclusions The results highlight that FTO is critical not only for body composition but also normal development, and its function might differ depending on the stage of development.

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Section: Discussionmentioning

confidence: 71%

The Fat Mass‐ and Obesity‐Associated (FTO) Gene to Obesity: Lessons from Mouse Models

Chang

Park

et al. 2018

Obesity

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“…Similar to ALKBH5, FTO is an RNA demethylase, removing the methyl group from modified adenosine . Up to now, it is known that FTO is involved in many biological processes, for example, cancer development, adipogenesis, or bone growth …”

Section: Impact Of Alkbh Proteins On Biological Processes In Higher Ementioning

confidence: 99%

“…FTO demethylation activity influences also a switch between adipogenic and osteogenic differentiation of Bone marrow‐derived mesenchymal stem cells . In later stages of growth, it sustains proper bone growth and maintains bone mass . In adult organism, FTO participates in regenerative processes following heart failure, through selective demethylation of cardiac contractile transcripts such as sarcoplasmic/endoplasmic reticulum calcium ATPase 2, myosin 6 or 7, and ryanodine receptor 2 .…”

Section: N6mea‐demethylases Participate In Cellular Regulatory Processesmentioning

confidence: 99%

“…In melanoma, tumorigenesis is caused by specific demethylation of mRNA of programmmed cell death protein 1, C‐X‐C chemokine receptor 4, and transcription factor SOX‐10. Moreover, for AML, gastric, endometrial, or HNSCC, this protein is involved in cancer development . An elevated FTO level is also responsible for chemotherapy resistance of cervical squamous cell carcinoma (Figure ).…”

Section: N6mea‐demethylases Participate In Cellular Regulatory Processesmentioning

confidence: 99%

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Human and Arabidopsis alpha‐ketoglutarate‐dependent dioxygenase homolog proteins—New players in important regulatory processes

et al. 2020

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The family of AlkB homolog (ALKBH) proteins, the homologs of Escherichia coli AlkB 2-oxoglutarate (2OG), and Fe(II)-dependent dioxygenase are involved in a number of important regulatory processes in eukaryotic cells including repair of alkylation lesions in DNA, RNA, and nucleoprotein complexes. There are nine human and thirteen Arabidopsis thaliana ALKBH proteins described, which exhibit diversified functions. Among them, human ALKBH5 and FaT mass and Obesity-associated (FTO) protein and Arabidopsis ALKBH9B and ALKBH10B have been recognized as N 6 methyladenine (N 6 meA) demethylases, the most abundant posttranscriptional modification in mRNA. The FTO protein is reported to be associated with obesity and type 2 diabetes, and involved in multiple other processes, while ALKBH5 is induced by hypoxia. Arabidopsis ALKBH9B is an N 6 meA demethylase influencing plant susceptibility to viral infections via m 6 A/A ratio control in viral RNA. ALKBH10B has been discovered to be a functional Arabidopsis homolog of FTO; thus, it is also an RNA N 6 meA demethylase involved in plant flowering and several other regulatory processes including control of metabolism. High-throughput mass spectrometry showed multiple sites of human ALKBH phosphorylation. In the case of FTO, the type of modified residue decides about the further processing of the protein. This modification may result in subsequent protein ubiquitination and proteolysis, or in the blocking of these processes. However, the impact of phosphorylation on the other ALKBH function and their downstream pathways remains nearly unexplored in both human and Arabidopsis. Therefore, the investigation of evolutionarily conserved functions of Abbreviations: (AlkB; FOXM1, Forkhead box protein M1; FTO, FaT mass and Obesity-associated; GWAS, genome-wide-associated studies; HIF-1alpha, hypoxia inducible factor 1; HNSCC, head and neck squamous cell carcinoma; IRX3, Iroquois-class homeodomain protein 3; mcm5U, 5-methoxycarbonylmethyluridine; MMS, mthyl methanosulphonate; N6meA, N6 methyladenine; NANOG, homeobox protein NANOG; PCNA, proliferating cell nuclear antigen; SNP, single nucleotide polymorphism; TBK1, TANK-binding kinase 1.Michał Marcinkowski and Tomaš Pilžys contributed equally to this study. Tomasz J. Sarnowski and Elzbieta Grzesiuk contributed equally to this study.

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“…A 305 previous study found that Rpgrip1l mutant mouse embryos displayed facial abnormalities in cleft 306 upper lips and hypoplastic lower jaws (Delous et al, 2007). FTO demethylase activity has been found 307 essential for normal bone growth and bone mineralization in mice (Sachse et al, 2018). TBX3, a 308 member of the T-box gene family, causes Ulnar-mammary syndrome which is a rare disorder 309 characterized by distinct chin and nose shape together with many other abnormal morphological 310 changes (Bamshad et al, 1997;Joss et al, 2011).…”

mentioning

confidence: 99%

Novel genetic loci affecting facial shape variation in humans

Xiong

Dankova

Lee³

et al. 2019

Preprint

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FTO demethylase activity is essential for normal bone growth and bone mineralization in mice

Cited by 25 publications

References 39 publications

The Fat Mass‐ and Obesity‐Associated (FTO) Gene to Obesity: Lessons from Mouse Models

The Fat Mass‐ and Obesity‐Associated (FTO) Gene to Obesity: Lessons from Mouse Models

Human and Arabidopsis alpha‐ketoglutarate‐dependent dioxygenase homolog proteins—New players in important regulatory processes

Novel genetic loci affecting facial shape variation in humans

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