2. Academic Validation
  3. The Zscan4-Tet2 Transcription Nexus Regulates Metabolic Rewiring and Enhances Proteostasis to Promote Reprogramming

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

  • Cell Rep. 2020 Jul 14;32(2):107877. doi: 10.1016/j.celrep.2020.107877.
Zhou-Li Cheng 1,  Meng-Li Zhang 2,  Huai-Peng Lin 3,  Chao Gao 1,  Jun-Bin Song 1,  Zhihong Zheng 4,  Linpeng Li 5,  Yanan Zhang 6,  Xiaoqi Shen 6,  Hao Zhang 7,  Zhenghui Huang 8,  Wuqiang Zhan 1,  Cheng Zhang 1,  Xu Hu 9,  Yi-Ping Sun 1,  Lubing Jiang 8,  Lei Sun 1,  Yanhui Xu 1,  Chen Yang 7,  Yuanlong Ge 10,  Yong Zhao 10,  Xingguo Liu 5,  Hui Yang 11,  Pengyuan Liu 12,  Xing Guo 6,  Kun-Liang Guan 13,  Yue Xiong 14,  Mingliang Zhang 15,  Dan Ye 16
Affiliations

Affiliations

  • 1 Huashan Hospital, Fudan University, and Molecular and Cell Biology Lab, the Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, and the Key Laboratory of Metabolism and Molecular, Ministry of Education, Shanghai, China; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Beijing, China.
  • 2 Huashan Hospital, Fudan University, and Molecular and Cell Biology Lab, the Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, and the Key Laboratory of Metabolism and Molecular, Ministry of Education, Shanghai, China; Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
  • 3 Medical College of Xiamen University, Xiamen 361102, China.
  • 4 Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China.
  • 5 The Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 6 Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
  • 7 Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China.
  • 8 Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
  • 9 Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Reproductive Medicine, Shanghai, China.
  • 10 MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 11 Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
  • 12 Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China.
  • 13 Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
  • 14 Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 15 Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Reproductive Medicine, Shanghai, China. Electronic address: mingliang.zhang@shsmu.edu.cn.
  • 16 Huashan Hospital, Fudan University, and Molecular and Cell Biology Lab, the Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, and the Key Laboratory of Metabolism and Molecular, Ministry of Education, Shanghai, China; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Beijing, China; Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: yedan@fudan.edu.cn.
PMID: 32668244 DOI: 10.1016/j.celrep.2020.107877
Abstract

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.

Keywords

SCAN domain; TET2; ZSCAN4; iPSCs; induced pluripotent stem cells; metabolic rewiring; proteasome function; stem cell potency.

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