DNA methylation is a crucial epigenetic modification in the establishment of cell-type-specific characteristics. However, how DNA methylation is selectively reprogrammed at adipocyte-specific loci during adipogenesis remains unclear. Here, we show that the transcription factor, C/EBPδ, and the DNA methylation eraser, TET3, cooperatively control adipocyte differentiation. We perform whole-genome bisulfite sequencing to explore the dynamics and regulatory mechanisms of DNA methylation in adipocyte differentiation. During adipogenesis, 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 catalyse DNA demethylation at the C/EBP binding motif and stimulate the expression of key adipogenic genes. Ectopic expression of TET3 potentiates in vitro and in vivo adipocyte differentiation and recovers downregulated adipogenic potential, which is observed in aged mice and humans. Taken 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.
Bibliographical noteFunding Information:
We thank K. Fujiki and M. Murata for providing the TET2 and TET3 vectors. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT; no. NRF-2018R1A5A1024340 to J.B.K. and J.P., 2020R1A3B2078617 to J.B.K. and NRF-2018R1A5A2024425 to S.H.C.).
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.