TET2 is recruited by CREB to promote Cebpb, Cebpa, and Pparg transcription by facilitating hydroxymethylation during adipocyte differentiation

Yunjia Liu; Ting He; Zhuofang Li; Zhen Sun; Shuai Wang; Huanming Shen; Lingfeng Hou; Shengnan Li; Yixin Wei; Bingzhao Zhuo; Shanni Li; Can Zhou; Huiling Guo; Rui Zhang; Boan Li

doi:10.1016/j.isci.2023.108312

TET2 is recruited by CREB to promote Cebpb, Cebpa, and Pparg transcription by facilitating hydroxymethylation during adipocyte differentiation

iScience. 2023 Oct 23;26(11):108312. doi: 10.1016/j.isci.2023.108312. eCollection 2023 Nov 17.

Authors

Yunjia Liu¹, Ting He¹, Zhuofang Li¹, Zhen Sun¹, Shuai Wang^{1

2}, Huanming Shen¹, Lingfeng Hou¹, Shengnan Li³, Yixin Wei¹, Bingzhao Zhuo¹, Shanni Li¹, Can Zhou¹, Huiling Guo¹, Rui Zhang⁴, Boan Li¹

Affiliations

¹ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network and Engineering Research Center of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian 361100, China.
² Department of Cardiology, Xiamen Key Laboratory of Cardiac Electrophysiology, Xiamen Institute of Cardiovascular Diseases, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
³ School of Medicine, Henan Polytechnic University, Jiaozuo, Henan 454000, China.
⁴ Xiamen Cell Therapy Research Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361003, China.

Abstract

Ten-eleven translocation proteins (TETs) are dioxygenases that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), an important epigenetic mark that regulates gene expression during development and differentiation. Here, we found that the TET2 expression was positively associated with adipogenesis. Further, in vitro and in vivo experiments showed that TET2 deficiency blocked adipogenesis by inhibiting the expression of the key transcription factors CCAAT/enhancer-binding protein beta (C/EBPβ), C/EBPα and peroxisome proliferator-activated receptor gamma (PPARγ). In addition, TET2 promoted 5hmC on the CpG islands (CGIs) of Cebpb, Cebpa and Pparg at the initial time point of their transcription, which requires the cAMP-responsive element-binding protein (CREB). At last, specific knockout of Tet2 in preadipocytes enabled mice to resist obesity and attenuated the obesity-associated insulin resistance. Together, TET2 is recruited by CREB to promote the expression of Cebpb, Cebpa and Pparg via 5hmC during adipogenesis and may be a potential therapeutic target for obesity and insulin resistance.

Keywords: Epigenetics; Molecular biology; Physiology.