The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+ T cells
The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+ T cells
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DOI：
10.1073/pnas.1920372117
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发表时间：
2020-08-25
影响因子：
11.1
通讯作者：
Jacobs, Heinz
中科院分区：
文献类型：
--
作者：
Kwesi-Maliepaard, Eliza Mari;Aslam, Muhammad Assad;Jacobs, Heinz
细胞毒性T细胞分化是由表观基因组适应引导的，但表观遗传机制如何控制淋巴细胞发育尚未得到很好的定义。本研究表明，组蛋白甲基转移酶DOT1L在活性基因上标记核小体核心，保护CD8(+) T细胞的正常分化。T细胞特异性消融DOT1L导致幼稚CD8(+) T细胞的丢失，并以细胞固有的方式向记忆样状态过早分化，不依赖抗原暴露。从机制上讲，DOT1L通过确保正常的T细胞受体密度和信号传导来控制CD8(+) T细胞分化。DOT1L也维持表观遗传特性，部分通过间接支持发育调节基因的抑制。最后，T细胞中DOT1L的缺失导致免疫应答受损。通过我们的研究，DOT1L正在成为CD8(+) T细胞生理学的核心参与者，作为防止过早分化和控制表观遗传完整性的屏障。
Cytotoxic T cell differentiation is guided by epigenome adaptations, but how epigenetic mechanisms control lymphocyte development has not been well defined. Here we show that the histone methyltransferase DOT1L, which marks the nucleosome core on active genes, safeguards normal differentiation of CD8(+) T cells. T cell-specific ablation of DOT1L resulted in loss of naive CD8(+) T cells and premature differentiation toward a memory-like state, independent of antigen exposure and in a cell-intrinsic manner. Mechanistically, DOT1L controlled CD8(+) T cell differentiation by ensuring normal T cell receptor density and signaling. DOT1L also maintained epigenetic identity, in part by indirectly supporting the repression of developmentally regulated genes. Finally, deletion of DOT1L in T cells resulted in an impaired immune response. Through our study, DOT1L is emerging as a central player in physiology of CD8(+) T cells, acting as a barrier to prevent premature differentiation and controlling epigenetic integrity.