2. Academic Validation
  3. Chemical-induced epigenome resetting for regeneration program activation in human cells

Chemical-induced epigenome resetting for regeneration program activation in human cells

  • Cell Rep. 2023 May 23;42(6):112547. doi: 10.1016/j.celrep.2023.112547.
Guan Wang 1,  Yanglu Wang 2,  Yulin Lyu 3,  Huanjing He 4,  Shijia Liuyang 4,  Jinlin Wang 4,  Shicheng Sun 4,  Lin Cheng 4,  Yao Fu 4,  Jialiang Zhu 4,  Xinxing Zhong 1,  Zhihan Yang 4,  Qijing Chen 4,  Cheng Li 5,  Jingyang Guan 6,  Hongkui Deng 7
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences and MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
  • 2 MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences and MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Academy for Advanced Interdisciplinary Studies, The Center for Biomed-X Research, Peking University, Beijing, China.
  • 3 School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China.
  • 4 MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences and MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
  • 5 School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China. Electronic address: cheng_li@pku.edu.cn.
  • 6 Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, China. Electronic address: guanjingyang@hsc.pku.edu.cn.
  • 7 MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences and MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China. Electronic address: hongkui_deng@pku.edu.cn.
PMID: 37224020 DOI: 10.1016/j.celrep.2023.112547
Abstract

Human somatic cells can be reprogrammed to pluripotent stem cells by small molecules through an intermediate stage with a regeneration signature, but how this regeneration state is induced remains largely unknown. Here, through integrated single-cell analysis of transcriptome, we demonstrate that the pathway of human chemical reprogramming with regeneration state is distinct from that of transcription-factor-mediated reprogramming. Time-course construction of chromatin landscapes unveils hierarchical histone modification remodeling underlying the regeneration program, which involved sequential enhancer recommissioning and mirrored the reversal process of regeneration potential lost in organisms as they mature. In addition, LEF1 is identified as a key upstream regulator for regeneration gene program activation. Furthermore, we reveal that regeneration program activation requires sequential enhancer silencing of somatic and proinflammatory programs. Altogether, chemical reprogramming resets the epigenome through reversal of the loss of natural regeneration, representing a distinct concept for cellular reprogramming and advancing the development of regenerative therapeutic strategies.

Keywords

CP: Stem cell research; activation of regeneration-like program; chemical reprogramming; enhancer recommissioning; epigenome remodeling; reboot regeneration potential.

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