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The Zscan4-Tet2 Transcription Nexus Regulates Metabolic Rewiring and Enhances Proteostasis to Promote Reprogramming

2020; Cell Press; Volume: 32; Issue: 2 Linguagem: Inglês

10.1016/j.celrep.2020.107877

2639-1856

Zhou‐Li Cheng, Mengli Zhang, Huaipeng Lin, Chao Gao, Junbin Song, Zhihong Zheng, Linpeng Li, Yanan Zhang, Xiaoqi Shen, Hao Zhang, Zhenghui Huang, Wuqiang Zhan, Cheng Zhang, Hu Xu, Yiping Sun, Lubing Jiang, Lei Sun, Yanhui Xu, Chen Yang, Yuanlong Ge, Yong Zhao, Xingguo Liu, Hui Yang, Pengyuan Liu, Xing Guo, Kun‐Liang Guan, Yue Xiong, Mingliang Zhang, Dan Ye,

CRISPR and Genetic Engineering

Evolutionarily conserved SCAN (named after SRE-ZBP, CTfin51, AW-1, and Number 18 cDNA)-domain-containing zinc finger transcription factors (ZSCAN) have been found in both mouse and human genomes. Zscan4 is transiently expressed during zygotic genome activation (ZGA) in preimplantation embryos and induced pluripotent stem cell (iPSC) reprogramming. However, little is known about the mechanism of Zscan4 underlying these processes of cell fate control. Here, we show that Zscan4f, a representative of ZSCAN proteins, is able to recruit Tet2 through its SCAN domain. The Zscan4f-Tet2 interaction promotes DNA demethylation and regulates the expression of target genes, particularly those encoding glycolytic enzymes and proteasome subunits. Zscan4f regulates metabolic rewiring, enhances proteasome function, and ultimately promotes iPSC generation. These results identify Zscan4f as an important partner of Tet2 in regulating target genes and promoting iPSC generation and suggest a possible and common mechanism shared by SCAN family transcription factors to recruit ten-eleven translocation (TET) DNA dioxygenases to regulate diverse cellular processes, including reprogramming.