Martin F J, Xu Y, Lohmann F, Ciccone D N, Nicholson T B, Loureiro J J, Chen T, Huang Q
Department of Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
Abbvie Bioresearch Center, Immunology Early Discovery, Worcester, MA, USA.
Genes Immun. 2015 Mar;16(2):162-9. doi: 10.1038/gene.2014.70. Epub 2015 Jan 8.
This work examines the role the lysine methyltransferase KMT1E (Setdb1) in thymocyte development. We have developed and described a T cell-specific conditional knockout of Setdb1. A partial block was seen at the double-positive to single-positive transition, causing reduced numbers of single-positive T cells in the thymus and periphery. Knockout thymocytes had reduced numbers of CD69(+) and T-cell receptor TCRβ(+) cells and increased numbers of apoptotic cells in the double-positive compartment, suggesting an alteration in the selection process. Transcriptional profiling of thymocytes revealed that Setdb1 deletion derepresses expression of FcγRIIb, the inhibitory Fc receptor. We demonstrate that a KMT1E-containing complex directly interacts with the FcγRIIb promoter and that histone H3 at lysine 9 tri-methylation at this promoter is dependent on Setdb1 expression. Derepression of FcγRIIb causes exacerbated signaling through the TCR complex, with specifically increased phosphorylation of ZAP70, affecting selection. This work identifies KMT1E as a novel repressor of FcγRIIb and identifies an underappreciated role of FcγRIIb in fine tuning thymocyte development.
这项研究探讨了赖氨酸甲基转移酶KMT1E（Setdb1）在胸腺细胞发育中的作用。我们构建并描述了Setdb1的T细胞特异性条件性敲除小鼠。在双阳性向单阳性转变阶段观察到部分阻滞，导致胸腺和外周单阳性T细胞数量减少。敲除胸腺细胞中双阳性区室的CD69(+)和T细胞受体TCRβ(+)细胞数量减少，凋亡细胞数量增加，提示选择过程发生改变。胸腺细胞的转录谱分析显示，Setdb1缺失会解除对抑制性Fc受体FcγRIIb表达的抑制。我们证明，含有KMT1E的复合物直接与FcγRIIb启动子相互作用，且该启动子赖氨酸9位点的组蛋白H3三甲基化依赖于Setdb1的表达。FcγRIIb的去抑制导致通过TCR复合物的信号增强，特别是ZAP70磷酸化增加，从而影响选择过程。这项研究确定KMT1E是FcγRIIb的新型抑制因子，并揭示了FcγRIIb在微调胸腺细胞发育中未被充分认识的作用。
