Molecular characterization of the role for metabolites in immune cell differentiation

摘要 代谢状态的动态调节在细胞分化决策中起着积极的作用，而这 发生在哺乳动物的整个发育过程中。这些过程在不同物种中的保守， 发育环境和免疫细胞类型表明新陈代谢影响常见的机械性事件 在不同的细胞背景下做出差异化决策所需的。然而，对这些的解读 保守机制必须具有细胞类型特异性的成分，才能适当地调节基因组 在各个蜂窝环境中促进适当的差异化。因此，定义 保守的和细胞类型特定的机制原理，以了解饮食和代谢干预如何 在健康和疾病状态下影响免疫细胞分化。在上一个供资周期中 在这笔赠款中，我们确定了α-酮戊二酸(αKG)在调节IL-2敏感基因程序中的作用。 T细胞。从机制上讲，αKG敏感事件增强了CTCFs与 CD4+T细胞，与对癌细胞的研究一起，数据表明这种整体活动在 细胞类型多样。数据还表明这些事件是以细胞类型特定的方式解释的， 可能基于细胞的增强子环境。在这笔赠款中，我们将扩大这些发现，以解决 如何选择αKG敏感的CTCF点，以及是否有任何依赖细胞类型的机制 选择这些站点。我们还将定义下游机制，如增强子活性，是否具有 对新陈代谢状态的敏感性。在这种情况下，我们将讨论增强器环境是否受 短链脂肪酸，如丁酸盐和醋酸酯。我们还将定义哪些方面的代谢物敏感 不同物种之间的机制是保守的，以及老鼠和人类基因组之间的差异 影响对保守的和细胞类型的特定事件的解释。从这些研究中获得的信息将 对预测代谢和饮食干预在免疫学治疗中的作用至关重要 或者在促进对传染病的有效免疫反应方面。

Abstract The dynamic regulation of metabolic states plays an active role in cellular differentiation decisions, and this occurs throughout mammalian development. The conservation of these processes in different species, developmental settings, and immune cell types suggests metabolism influences common mechanistic events needed for differentiation decisions in diverse cellular backgrounds. However, the interpretation of these conserved mechanisms must have a component of cell-type specificity to properly regulate the genome to promote appropriate differentiation in individual cellular settings. Therefore, it is important to define the conserved and cell-type specific mechanistic principles to understand how dietary and metabolic interventions influence immune cell differentiation in the context of healthy and disease states. In the previous funding cycle of this grant, we identified a role for alpha-ketoglutarate (αKG) in regulating the IL-2-sensitive gene program in T cells. Mechanistically, αKG-sensitive events enhanced the association of CTCF with a subset of sites in CD4+ T cells, and together with studies in cancer cells, the data indicated this overall activity is conserved in diverse cell-types. The data also suggested these events are interpreted in a cell-type specific manner, potentially based on the enhancer landscape of the cell. In this grant, we will extend these findings to address how αKG-sensitive CTCF sites are selected, and whether there are any cell-type dependent mechanisms selecting these sites. We will also define whether downstream mechanisms, such as enhancer activity, have sensitivity to metabolic states. In this context, we will address whether the enhancer landscape is regulated by short chain fatty acids such as butyrate and acetate. We will also define which aspects of metabolite-sensitive mechanisms are conserved between species, and how variation between the mouse and human genome influences the interpretation of conserved and cell-type specific events. Information gained in these studies will be critical for predicting the role for metabolic and dietary interventions in the treatment of immunological diseases or in promoting effective immune responses to infectious diseases.