Liu Qiao, Dong Wei, Liu Rong, Xu Luming, Ran Ling, Xie Ziying, Lei Shun, Su Xingxing, Yue Zhengliang, Xiong Dan, Wang Lisha, Wen Shuqiong, Zhang Yan, Hu Jianjun, Qin Chenxi, Chen Yongchang, Zhu Bo, Chen Xiangyu, Wu Xia, Xu Lifan, Huang Qizhao, Cao Yingjiao, Ye Lilin, Tang Zhonghui
Department of Hematology and Oncology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing 400014, China.
Institute of Immunology, Third Military Medical University, Chongqing 400038, China.
Protein Cell. 2025 Jul 19;16(7):575-601. doi: 10.1093/procel/pwaf003.
Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
广泛的表观遗传重编程参与记忆性CD8+ T细胞的分化。CD8+ T细胞异质性功能状态背后复杂的表观遗传重塑仍不为人知。在这里，我们分析单细胞染色质可及性并绘制增强子-启动子相互作用组图谱，以表征记忆性CD8+ T细胞的分化轨迹。我们发现，在不同的表观遗传调控下，早期活化的CD8+ T细胞分化为短命效应细胞和记忆前体效应细胞。我们还揭示了在记忆形成过程中，从效应记忆细胞向中央记忆细胞转化所涉及的特定表观遗传重塑。此外，我们阐明了记忆分化过程中持久与短暂转录调控背后的染色质调控机制。最后我们证实，Sox4和Nrf2分别在记忆前体效应细胞和效应记忆细胞的发育中起关键作用，并使用CRISPR-Cas9验证了细胞状态特异性增强子对Il7r的调控作用。我们的数据为理解CD8+ T细胞分化过程中表观遗传记忆形成的机制铺平了道路。
