Targeted Erasure of DNA Methylation by TET3 with C/EBP delta Rewires Adipogenic Execution for Energy Metabolism

DNA methylation is one of the key epigenetic modifications in the establishment of cell-type-specific characteristics. However, how DNA methylation is selectively regulated at adipocyte-specific loci during adipogenesis remains unclear. We have demonstrated that the transcription factor, C/EBPδ, and the DNA methylation eraser, TET3, cooperatively control adipocyte differentiation. We performed whole-genome bisulfite sequencing to explore the DNA methylation in adipocyte differentiation. Intriguingly, DNA methylation selectively decreases at adipocyte-specific loci carrying the C/EBP binding motif, which correlates with the activity of adipogenic promoters and enhancers. Mechanistically, we find that C/EBPδ recruits a DNA methylation eraser, TET3, to catalyze DNA demethylation and stimulate the expression of key adipogenic genes. Ectopic expression of TET3 potentiates in vitro and in vivo adipocyte differentiation and restores insulin sensitivity and decreased adipogenic potential, which is observed in aged mice and humans. Together, our study highlights how targeted reprogramming of DNA methylation through cooperative action of the transcription factor C/EBPδ, and the DNA methylation eraser TET3, controls adipocyte differentiation for whole body energy metabolism. Disclosure J.Park: None. J.Kim: None. Funding National Research Foundation of Korea (2018R1A5A1024340 to J.B.K. and J.P), (2020R1A3B2078617 to J.B.K)