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定中起着积极的作用，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存， 发育环境和免疫细胞类型表明代谢影响常见的机械事件 需要在不同的细胞背景的分化决定。然而，这些解释 保守机制必须具有细胞类型特异性的成分，以适当地调节基因组， 促进个体细胞环境中的适当分化。因此，定义 保守和细胞类型特异性的机械原理，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， 在这项研究中，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，α KG敏感性事件增强了CTCF与以下部位子集的相关性： CD 4 + T细胞，以及在癌细胞中的研究，数据表明这种总体活性在肿瘤细胞中是保守的。 不同的细胞类型。数据还表明，这些事件是以细胞类型特异性方式解释的， 潜在地基于细胞的增强子景观。在这次赠款中，我们将扩大这些发现，以解决 如何选择α KG敏感的CTCF位点，以及是否存在任何细胞类型依赖性机制 选择这些网站。我们还将确定下游机制，如增强子活性，是否具有 对代谢状态的敏感性。在这种情况下，我们将讨论增强子景观是否受到以下因素的调控： 短链脂肪酸，如丁酸盐和乙酸盐。我们还将定义代谢敏感性的哪些方面 机制在物种之间是保守的，以及小鼠和人类基因组之间的变异 影响保守和细胞类型特异性事件的解释。从这些研究中获得的信息将 对于预测代谢和饮食干预在免疫性疾病治疗中的作用至关重要。 疾病或促进对传染病的有效免疫应答。

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.