Metabolic regulation of epigenetic asymmetry in CD8 T lymphocytes

CD8T淋巴细胞能够经历不对称的细胞分裂，导致两个子代细胞群，它们的新陈代谢以及它们的命运和功能不同。从免疫突触近端的细胞长出的子代细胞表现出更多的效应型，而起源于远端细胞的子代细胞则更具记忆性。引人注目的是，这两个细胞群体在表观遗传特征上也不同。例如，近端子细胞显示颗粒酶B启动子的去甲基化增强(这是基因表达活跃的迹象)，颗粒酶B启动子是效应器T淋巴细胞的关键角色，这与流感病毒感染期间该细胞群体的效应器样表型一致。这提出了一种耐人寻味的可能性，即T淋巴细胞的命运在其第一次通过蛋白质和营养梯度分裂之前预先设定，通过代谢物传递，最终印记在表观基因组中。因此，该项目旨在研究这样的假设：i)第一分裂CD8 T淋巴细胞的不对称表观遗传特征是通过代谢建立和维持的，以及ii)这些细胞的命运可以通过操纵表观遗传印记来改变。我们认为，氨基酸转运体的不对称排列是T细胞激活后的早期事件，导致氨基酸梯度和TORC1活性极化。当T细胞经历第一次分裂时，代谢产物的不对称可获得性可能导致表观遗传酶活性的不同水平，这可能是观察到的第一次分裂T细胞不对称去甲基化的原因。此外，c-Myc在两个子代中的不同水平可能通过影响代谢酶的表达水平来促进代谢物的可获得性，或者可能直接作用于增加表观遗传酶的表达。此外，拟议的项目旨在通过调节氨基酸转运体、TORC1信号组件或c-Myc的表达来研究DNA甲基化在维持不对称性中的作用。最后，我们将测试差异表观遗传特征和细胞命运可以通过定向新陈代谢过程来操纵的想法。

CD8 T lymphocytes are able to undergo asymmetric cell division, which results in two daughter cell populations, differing in their metabolism as well as in their fate and function. Daughter cells that rise from the cell proximal to the immunological synapse show a more effector-like phenotype whereas daughter cells originating from the distal cell are more memory-like. Strikingly, the two cell populations also differ in their epigenetic signature. For example, the proximal daughter cell shows enhanced demethylation (an indication for active gene expression) of the Granzyme B promoter, a key player in effector T lymphocytes, which is in line with the effector-like phenotype of this cell population during influenza virus infection. This raises the intriguing possibility that the fate of a T lymphocyte is preset prior to its first division by protein and nutrient gradients, transmitted through metabolites, to be finally imprinted into the epigenome. Therefore, the proposed project aims to investigate the hypothesis that i) the asymmetric epigenetic signature of first division CD8 T lymphocytes is established and maintained metabolically and ii) that the fate of these cells can be modified by manipulating the epigenetic imprint. We propose that asymmetric arrangement of amino acid transporters as an early event following T cell activation results in an amino acid gradient and polarized TORC1 activity. As the T cell undergoes its first division, asymmetric availability of metabolites might result in differential levels of activity of epigenetic enzymes, which might account for the observed asymmetric demethylation in first division T cells. Also, a differential level of c-Myc in the two daughters might contribute to availability of metabolites by affecting the expression level of metabolic enzymes or may act to increase the expression of epigenetic enzymes directly. Further, the proposed project aims to investigate the role of DNA methylation in the maintenance of asymmetry by regulating the expression of amino acid transporters, TORC1 signaling components, or c-Myc. Finally, we will test the idea that differential epigenetic signatures and cell fate can be manipulated by targeting metabolic processes.