Stengel Kristy R, Zhao Yue, Klus Nicholas J, Kaiser Jonathan F, Gordy Laura E, Joyce Sebastian, Hiebert Scott W, Summers Alyssa R
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Department of Biology, The University of the South: Sewanee, Sewanee, Tennessee, USA.
Mol Cell Biol. 2015 Nov;35(22):3854-65. doi: 10.1128/MCB.00706-15. Epub 2015 Aug 31.
Hdac3 is a key target for Hdac inhibitors that are efficacious in cutaneous T cell lymphoma. Moreover, the regulation of chromatin structure is critical as thymocytes transition from an immature cell with open chromatin to a mature T cell with tightly condensed chromatin. To define the phenotypes controlled by Hdac3 during T cell development, we conditionally deleted Hdac3 using the Lck-Cre transgene. This strategy inactivated Hdac3 in the double-negative stages of thymocyte development and caused a significant impairment at the CD8 immature single-positive (ISP) stage and the CD4/CD8 double-positive stage, with few mature CD4(+) or CD8(+) single-positive cells being produced. When Hdac3(-/-) mice were crossed with Bcl-xL-, Bcl2-, or TCRβ-expressing transgenic mice, a modest level of complementation was found. However, when the null mice were crossed with mice expressing a fully rearranged T cell receptor αβ transgene, normal levels of CD4 single-positive cells were produced. Thus, Hdac3 is required for the efficient transit from double-negative stage 4 through positive selection.
Hdac3是对皮肤T细胞淋巴瘤有效的Hdac抑制剂的关键靶点。此外，随着胸腺细胞从不成熟的开放染色质细胞转变为成熟的紧密凝聚染色质T细胞，染色质结构的调控至关重要。为了确定Hdac3在T细胞发育过程中控制的表型，我们使用Lck-Cre转基因有条件地删除了Hdac3。该策略在胸腺细胞发育的双阴性阶段使Hdac3失活，并在CD8未成熟单阳性（ISP）阶段和CD4/CD8双阳性阶段导致显著损伤，产生的成熟CD4(+)或CD8(+)单阳性细胞很少。当Hdac3(-/-)小鼠与表达Bcl-xL、Bcl2或TCRβ的转基因小鼠杂交时，发现有适度的互补作用。然而，当敲除小鼠与表达完全重排的T细胞受体αβ转基因的小鼠杂交时，产生了正常水平的CD4单阳性细胞。因此，Hdac3是双阴性4期通过阳性选择有效过渡所必需的。
