Targeted erasure of DNA methylation by TET3 drives adipogenic reprogramming and differentiation

Jeu Park, Do Hoon Lee, Seokjin Ham, Jiyoung Oh, Jung Ran Noh, Yun Kyung Lee, Yoon Jeong Park, Gung Lee, Sang Mun Han, Ji Seul Han, Ye Young Kim, Yong Geun Jeon, Han Nahmgoong, Kyung Cheul Shin, Sung Min Kim, Sung Hee Choi, Chul Ho Lee, Jiyoung Park, Tae Young Roh, Sun KimJae Bum Kim

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)918-931
Number of pages14
JournalNature Metabolism
Volume4
Issue number7
DOIs
StatePublished - Jul 2022

Bibliographical note

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© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

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