The RNA demethylase FTO is required for maintenance of bone mass and functions to protect osteoblasts from genotoxic damage

作者：Qian Zhang, Ryan C. Riddle, Qian Yang, Clifford R. Rosen, Denis C. Guttridge, Naomi Dirckx, Marie–Claude Faugere, Charles R. Farber, Thomas L. Clemens · 发表于：Proceedings of the National Academy of Sciences · 年份：2019 · DOI：10.1073/pnas.1905489116 · 被引用次数：131 · 研究领域：RNA modifications and cancer、RNA Research and Splicing、Cancer-related molecular mechanisms research

Significance Like other complex disorders, such as diabetes and obesity, osteoporosis is strongly influenced by genetic factors. In this study, we explored the function of the fat mass and obesity-associated gene (FTO), an RNA demethyase that has been strongly linked by genome-wide association studies to obesity and bone density. We show that loss of Fto in mouse osteoblasts leads to age-related bone loss with increased susceptibility of osteoblasts to cell death. RNA profiling of osteoblasts lacking Fto prioritized FTO targets that are members of the DNA repair pathway, which are activated in response to genotoxic stimuli. Our results identify an epigenetic pathway in which FTO normally functions in bone to enhance the stability of mRNA-encoding proteins that protect osteoblasts from genotoxic damage.