Active Demethylation of the Foxp3 Locus Leads to the Generation of Stable Regulatory T Cells within the Thymus
Active Demethylation of the Foxp3 Locus Leads to the Generation of Stable Regulatory T Cells within the Thymus
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DOI：
10.4049/jimmunol.1203473
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发表时间：
2013-04-01
影响因子：
4.4
通讯作者：
Huehn, Jochen
中科院分区：
文献类型：
--
作者：
Toker, Aras;Engelbert, Dirk;Huehn, Jochen
Foxp 3在调节性T细胞（Tcells）中的稳定表达依赖于Treg特异性去甲基化区（TSDR）的DNA去甲基化，TSDR是Foxp 3基因座内保守的富含CpG的区域。TSDR在从次级淋巴器官纯化的离体Treg中选择性地去甲基化，但不清楚在Treg发育的哪个阶段发生去甲基化。在这项研究中，我们表明，承诺一个稳定的谱系发生在小鼠胸腺Treg发展的早期阶段，通过雕刻的谱系特异性表观遗传标记与Treg特异性基因表达谱的建立并行。TSDR去甲基化是通过一种主动机制实现的，涉及10 - 11-易位家族的酶和甲基化胞嘧啶的羟基化，这种修饰被认为是有丝分裂非依赖性DNA去甲基化途径的起始步骤，但在免疫细胞分化期间的特定位点尚未观察到。总之，我们的结果表明，在胸腺Treg发育的早期阶段启动TSDR去甲基化开始稳定Foxp 3表达，并保证TSDR的完整功能和长期谱系稳定性。免疫学杂志，2013，190：3180-3188。
Stable expression of Foxp3 in regulatory T cells (Tregs) depends on DNA demethylation at the Treg-specific demethylated region (TSDR), a conserved, CpG-rich region within the Foxp3 locus. The TSDR is selectively demethylated in ex vivo Tregs purified from secondary lymphoid organs, but it is unclear at which stage of Treg development demethylation takes place. In this study, we show that commitment to a stable lineage occurred during early stages of murine thymic Treg development by engraving of lineage-specific epigenetic marks in parallel with establishment of a Treg-specific gene expression profile. TSDR demethylation was achieved through an active mechanism and involved enzymes of the ten-eleven-translocation family and hydroxylation of methylated cytosines, a modification that is implicated as an initiating step of mitosis-independent DNA demethylation pathways and has not yet been observed at specific loci during immune cell differentiation. Together, our results demonstrate that initiating TSDR demethylation during early stages of thymic Treg development commences stabilization of Foxp3 expression and guarantees full functionality and long-term lineage stability of Tregs. The Journal of Immunology, 2013, 190: 3180-3188.