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

Zhou-Li Cheng; Meng-Li Zhang; Huai-Peng Lin; Chao Gao; Jun-Bin Song; Zhihong Zheng; Linpeng Li; Yanan Zhang; Xiaoqi Shen; Hao Zhang; Zhenghui Huang; Wuqiang Zhan; Cheng Zhang; Xu Hu; Yi-Ping 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

doi:10.1016/j.celrep.2020.107877

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.

Authors

Zhou-Li Cheng¹, Meng-Li Zhang², Huai-Peng Lin³, Chao Gao¹, Jun-Bin Song¹, Zhihong Zheng⁴, Linpeng Li⁵, Yanan Zhang⁶, Xiaoqi Shen⁶, Hao Zhang⁷, Zhenghui Huang⁸, Wuqiang Zhan¹, Cheng Zhang¹, Xu Hu⁹, Yi-Ping Sun¹, Lubing Jiang⁸, Lei Sun¹, Yanhui Xu¹, Chen Yang⁷, Yuanlong Ge¹⁰, Yong Zhao¹⁰, Xingguo Liu⁵, Hui Yang¹¹, Pengyuan Liu¹², Xing Guo⁶, Kun-Liang Guan¹³, Yue Xiong¹⁴, Mingliang Zhang¹⁵, Dan Ye¹⁶

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Cellular Reprogramming / genetics*
DNA / metabolism
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Dioxygenases
Glycolysis / genetics
HEK293 Cells
Humans
Induced Pluripotent Stem Cells / metabolism
MCF-7 Cells
Mice, Inbred C57BL
Proteasome Endopeptidase Complex / metabolism
Protein Binding
Protein Domains
Proteostasis / genetics*
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*
Transcription Factors / metabolism*
Transcription, Genetic*
Up-Regulation

Substances

DNA-Binding Proteins
Proto-Oncogene Proteins
Transcription Factors
ZSCAN4 protein, human
DNA
Dioxygenases
TET2 protein, human
Tet2 protein, mouse
Proteasome Endopeptidase Complex