Foxp3 orchestrates reorganization of chromatin architecture to establish regulatory T cell identity.
Foxp3 orchestrates reorganization of chromatin architecture to establish regulatory T cell identity.
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DOI：
10.1038/s41467-023-42647-y
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发表时间：
2023-11-06
影响因子：
16.6
通讯作者：
Dixon, Jesse R.
中科院分区：
文献类型：
--
作者：
Liu, Zhi;Lee, Dong-Sung;Liang, Yuqiong;Zheng, Ye;Dixon, Jesse R.
染色质构象重组正在成为基因表达和谱系特化的重要调控层。然而，谱系特异性转录因子如何有助于在免疫细胞中建立细胞类型特异性3D染色质结构仍不清楚，特别是对于T细胞亚群分化和成熟的后期阶段。调节性T细胞（Treg）主要在胸腺中产生，作为专门抑制过度免疫应答的T细胞亚群。在这里，通过全面绘制Treg细胞分化过程中的3D染色质组织，我们表明Treg特异性染色质结构在其谱系特化过程中逐渐建立，并且与Treg签名基因表达高度相关。此外，Foxp 3的结合位点，Treg谱系特异性转录因子，高度富集在Treg特异性染色质环锚。对来自Foxp 3敲入/敲除或新产生的Foxp 3结构域交换突变小鼠的野生型TcB与Treg细胞之间的染色质相互作用的进一步比较揭示，Foxp 3对于Treg特异性3D染色质结构的建立是必不可少的，尽管它不依赖于Foxp 3结构域交换二聚体的形成。这些结果强调了Foxp 3在调节Treg特异性3D染色质结构形成中的未被充分认识的作用。细胞谱系特化涉及大量的染色质构象重组。在这里，作者整合了原位Hi-C和PLAC-seq来绘制Treg细胞分化过程中3D染色质结构的动态变化。此外，作者进一步表征了Foxp 3在不同Foxp 3突变小鼠系建立Treg特异性染色质相互作用中的作用。
Chromatin conformation reorganization is emerging as an important layer of regulation for gene expression and lineage specification. Yet, how lineage-specific transcription factors contribute to the establishment of cell type-specific 3D chromatin architecture in the immune cells remains unclear, especially for the late stages of T cell subset differentiation and maturation. Regulatory T cells (Treg) are mainly generated in the thymus as a subpopulation of T cells specializing in suppressing excessive immune responses. Here, by comprehensively mapping 3D chromatin organization during Treg cell differentiation, we show that Treg-specific chromatin structures were progressively established during its lineage specification, and highly associated with Treg signature gene expression. Additionally, the binding sites of Foxp3, a Treg lineage specifying transcription factor, were highly enriched at Treg-specific chromatin loop anchors. Further comparison of the chromatin interactions between wide-type Tregs versus Treg cells from Foxp3 knock-in/knockout or newly-generated Foxp3 domain-swap mutant mouse revealed that Foxp3 was essential for the establishment of Treg-specific 3D chromatin architecture, although it was not dependent on the formation of the Foxp3 domain-swapped dimer. These results highlighted an underappreciated role of Foxp3 in modulating Treg-specific 3D chromatin structure formation. Cell lineage specification involves substantial chromatin conformation reorganization. Here, the authors integrate in-situ Hi-C and PLAC-seq to map the dynamic changes in 3D chromatin structure during Treg cell differentiation. Furthermore, the authors further characterize the role of Foxp3 in the establishment of Treg-specific chromatin interactions by different Foxp3-mutant mouse lines.
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影响因子：
32.4
作者：
Hu G;Cui K;Fang D;Hirose S;Wang X;Wangsa D;Jin W;Ried T;Liu P;Zhu J;Rothenberg EV;Zhao K
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通讯作者：
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影响因子：
32.4
作者：
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通讯作者：
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