Epigenetic Regulation by FoxO1 in Pancreatic Beta Cells

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Project Summary Over the last 30 years, diabetes has become a pandemic. Type 2 diabetes is the most common form of diabetes, and pancreatic β cell failure is pivotal in the pathogenesis of this metabolic disorder. Restoring β cell function has taken center stage in developing therapeutics to “cure” diabetes, through inducing β cell proliferation, re-differentiation, and regeneration. However, the quality and quantity of “β cell” obtained are less than ideal. One critical aspect to facilitate these processes to generating “perfect” β cell is to understand the epigenetic changes involved in β cell formation and maintenance. More and more evidence suggests that histone modification and chromatin remodeling play critical roles in β cell development, cell fate commitment, proliferation, and regeneration. Key β cell transcription factor FoxO1 is required to maintain β cell maturity. Ablation of FoxO1 in β cells leads to β cell dedifferentiation, a process where mature β cells lose their identity and ability to produce and secret insulin. In healthy β cells, FoxO1 is inactive and resides in the cytoplasm. In response to stressors, such as aging and multiparity, FoxO1 translocates into the nucleus, and elicits transcriptional networks to defend β cell health. In advanced type 2 diabetes, FoxO1 disappears from β cells as a result of increased degradation, leading to metabolic inflexibility and paving the way for dedifferentiation. However, whether the protective role of FoxO1 against β cell failure involves maintaining the epigenomic landscape has not been studied. The proposed studies will fill the gap of knowledge between FoxO1, epigenetics, functional genomics, and diabetes. The PI presented preliminary data to establish a role of FoxO1 in epigenetics with RNAseq and histone modification ChIPseq (i.e., H3K4me3, H3K27me3, and H3K27ac) using FAC sorted β cells in β cell-specific FoxO1 KO mice. The PI will continue to build the integrative regulatory map of FoxO1 in pancreatic β-cell with Hi-C, DNA methylation, and FoxO1 ChIPseq. H3K27ac motif analysis and RNA profiling suggest an imbalanced regulation between FoxO1 and Hnf4α, therefore, the PI will perform glucose clamps, glucose tolerance test, glucose- and arginine-stimulated insulin secretion in isolated islets, and RNAseq using β cell-specific FoxO1 and Hnf4α double KO mice to determine the epistasis of FoxO1 and Hnf4α. The PI will also functionally characterize FoxO1 targets to identify genes of therapeutic interest. The tailored research training and career development activities will assist the PI to achieve her career goals: becoming an independent academic investigator and advancing the field of diabetes research.