Fat Mass and Obesity Associated Gene FTO Expression Is Regulated Negatively by the Transcription Factor Foxa2Reportar como inadecuado




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Fat mass and obesity associated gene FTO is the first gene associated with body mass index BMI and risk for diabetes. FTO is highly expressed in the brain and pancreas, and is involved in regulating dietary intake and energy expenditure. To investigate the transcriptional regulation of FTO expression, we created 5′-deletion constructs of the FTO promoter to determine which transcription factors are most relevant to FTO expression. The presence of an activation region at −201-+34 was confirmed by luciferase activity analysis. A potential Foxa2 called HNF-3β binding site and an upstream stimulatory factor USF-binding site was identified in the −100 bp fragment upstream of the transcription start site TSS. Furthermore, using mutagenesis, we identified the Foxa2 binding sequence −26-−14 as a negative regulatory element to the activity of the human FTO promoter. The USF binding site did not affect the FTO promoter activity. Chromatin immunoprecipitation ChIP assays were performed to confirm Foxa2 binding to the FTO promoter. Overexpression of Foxa2 in HEK 293 cells significantly down-regulated FTO promoter activity and expression. Conversely, knockdown of Foxa2 by siRNA significantly up-regulated FTO expression. These findings suggest that Foxa2 negatively regulates the basal transcription and expression of the human FTO gene.



Autor: Jianjin Guo, Wei Ren, Ying Ding, Aimei Li, Lu Jia, Dongming Su, Xiang Liu, Kuanfeng Xu, Tao Yang

Fuente: http://plos.srce.hr/



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