Department of Dermatology, Second Xiangya Hospital, Central South University, #139 Renmin Middle Road, Changsha, 410011, Hunan, China.
Research Unit of Key Technologies of Diagnosis and Treatment for Immune-Related Skin Diseases, Chinese Academy of Medical Sciences (2019RU027), Changsha, Hunan, China.
Clin Epigenetics. 2021 Feb 10;13(1):31. doi: 10.1186/s13148-021-01007-7.
Transcription factor B cell lymphoma 6 (BCL6) is a master regulator of T follicular helper (Tfh) cells, which play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). However, the mechanisms by which BCL6 expression is regulated are poorly understood. Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an important epigenetic factor that regulates DNA methylation and histone modifications. In the present study, we assessed whether UHRF1 can regulate BCL6 expression and influence the differentiation and proliferation of Tfh cells.
Compared to healthy controls, the mean fluorescence intensity of UHRF1 (UHRF1-MFI) in Tfh cells from SLE patients was significantly downregulated, whereas that of BCL6 (BCL6-MFI) was significantly upregulated. In vitro, UHRF1 knockdown led to BCL6 overexpression and promoted Tfh cell differentiation. In contrast, UHRF1 overexpression led to BCL6 downregulation and decreased Tfh cell differentiation. In vivo, conditional UHRF1 gene knockout (UHRF1-cKO) in mouse T cells revealed that UHRF1 depletion can enhance the proportion of Tfh cells and induce an augmented GC reaction in mice treated with NP-keyhole limpet hemocyanin (NP-KLH). Mechanistically, UHRF1 downregulation can decrease DNA methylation and H3K27 trimethylation (H3K27me3) levels in the BCL6 promoter region of Tfh cells.
Our results demonstrated that UHRF1 downregulation leads to increased BCL6 expression by decreasing DNA methylation and H3K27me3 levels, promoting Tfh cell differentiation in vitro and in vivo. This finding reveals the role of UHRF1 in regulating Tfh cell differentiation and provides a potential target for SLE therapy.
转录因子 B 细胞淋巴瘤 6（BCL6）是 T 滤泡辅助（Tfh）细胞的主要调节因子，在系统性红斑狼疮（SLE）的发病机制中起着至关重要的作用。然而，BCL6 表达的调控机制尚不清楚。泛素样含 PHD 和 RING 指结构域蛋白 1（UHRF1）是一种重要的表观遗传因子，可调节 DNA 甲基化和组蛋白修饰。在本研究中，我们评估了 UHRF1 是否可以调节 BCL6 的表达，并影响 Tfh 细胞的分化和增殖。
与健康对照组相比，SLE 患者 Tfh 细胞中 UHRF1 的平均荧光强度（UHRF1-MFI）明显下调，而 BCL6 的平均荧光强度（BCL6-MFI）明显上调。体外，UHRF1 敲低导致 BCL6 过表达并促进 Tfh 细胞分化。相反，UHRF1 过表达导致 BCL6 下调并减少 Tfh 细胞分化。体内，在小鼠 T 细胞中条件性敲除 UHRF1 基因（UHRF1-cKO）显示，UHRF1 耗竭可增加 Tfh 细胞的比例，并在用 NP-血蓝蛋白（NP-KLH）处理的小鼠中诱导增强的 GC 反应。机制上，UHRF1 下调可降低 Tfh 细胞 BCL6 启动子区域的 DNA 甲基化和 H3K27 三甲基化（H3K27me3）水平。
我们的结果表明，UHRF1 下调通过降低 DNA 甲基化和 H3K27me3 水平导致 BCL6 表达增加，促进体外和体内 Tfh 细胞分化。这一发现揭示了 UHRF1 在调节 Tfh 细胞分化中的作用，并为 SLE 治疗提供了一个潜在的靶点。
