Lai Xin, Li Caizhi, Tang Xinglinzi, Luo Xinyi, Wu Feiyan, Liang Yuhong, Huang Bihui, Li Hang
The Seventh Clinical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China.
Shenzhen Bao'an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China.
Front Immunol. 2025 Aug 15;16:1652398. doi: 10.3389/fimmu.2025.1652398. eCollection 2025.
Super-enhancers (SEs) are dynamic chromatin structures that function as epigenetic hubs, orchestrating cell-type-specific transcriptional programs crucial for immune cell differentiation, functional specialization, and adaptive responses. These enhancer clusters integrate transcription factor (TF) networks, chromatin-modifying signals, and three-dimensional genome organization to govern lineage commitment, effector function acquisition, and metabolic reprogramming while enabling plasticity in response to environmental cues. SEs exhibit spatiotemporal regulatory properties, such as chromatin looping, phase-separated condensate formation, and stimulus-driven enhancer-promoter rewiring, all of which stabilize transcriptional outputs vital for immune homeostasis. Pathological dysregulation of SEs disrupts immune tolerance and amplifies aberrant transcriptional circuits, contributing to immune-mediated diseases marked by chronic inflammation, autoimmunity, or malignancy. Emerging therapeutic strategies targeting SE-associated components show promise in dismantling pathogenic enhancer networks through CRISPR-based editing, small-molecule inhibitors, and proteolysis-targeting chimeras(PROTACs). However, challenges remain in achieving therapeutic specificity amidst the dynamic reorganization of SEs and ensuring cell-type-selective delivery. By providing insights into SE-driven chromatin dynamics and transcriptional control in health and disease, this review focuses on two central questions: whether SEs causally drive immune cell fate decisions, and how they function within shared core transcriptional regulatory networks across cancer, infection, and autoimmune diseases. Future advances in multi-omics profiling, single-cell resolution analyses, and combinatorial therapeutic strategies will be critical for translating SE biology into precision interventions that restore immune equilibrium in dysregulated conditions.
超级增强子（SEs）是动态染色质结构，作为表观遗传枢纽发挥作用，协调对免疫细胞分化、功能特化和适应性反应至关重要的细胞类型特异性转录程序。这些增强子簇整合转录因子（TF）网络、染色质修饰信号和三维基因组组织，以控制谱系定向、效应器功能获得和代谢重编程，同时在响应环境线索时实现可塑性。SEs表现出时空调节特性，如染色质环化、相分离凝聚物形成和刺激驱动的增强子-启动子重连，所有这些都稳定了对免疫稳态至关重要的转录输出。SEs的病理性失调会破坏免疫耐受并放大异常转录回路，导致以慢性炎症、自身免疫或恶性肿瘤为特征的免疫介导疾病。针对SE相关成分的新兴治疗策略显示出通过基于CRISPR的编辑、小分子抑制剂和蛋白酶靶向嵌合体（PROTACs）拆解致病性增强子网络的前景。然而，在SEs动态重组过程中实现治疗特异性以及确保细胞类型选择性递送方面仍存在挑战。通过深入了解健康和疾病中SE驱动的染色质动力学和转录控制，本综述聚焦于两个核心问题：SEs是否因果性驱动免疫细胞命运决定，以及它们在癌症、感染和自身免疫性疾病的共享核心转录调控网络中如何发挥作用。多组学分析、单细胞分辨率分析和联合治疗策略的未来进展对于将SE生物学转化为在失调条件下恢复免疫平衡的精准干预至关重要。
