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.
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.
Cell Rep. 2023 Jun 27;42(6):112547. doi: 10.1016/j.celrep.2023.112547. Epub 2023 May 23.
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.
人类体细胞可以通过小分子在具有再生特征的中间阶段被重编程为多能干细胞，但这种再生状态是如何诱导的仍然很大程度上未知。在这里，通过对转录组的单细胞进行综合分析，我们证明了具有再生状态的人类化学重编程的途径与转录因子介导的重编程途径不同。染色质景观的时程构建揭示了再生程序背后的层次组蛋白修饰重塑，其中涉及顺序增强子重新分配，并且反映了生物体在成熟过程中再生潜力丧失的逆转过程。此外，鉴定出 LEF1 是再生基因程序激活的关键上游调节剂。此外，我们揭示了再生程序的激活需要体细胞和促炎程序的顺序增强子沉默。总之，化学重编程通过逆转自然再生的丧失来重置表观基因组，代表了细胞重编程的一个独特概念，并推进了再生治疗策略的发展。
