Eavesdropping on the conversation between chromatin and metabolism

摘要 过去几十年的研究揭示了精确调控基因组的表观遗传机制。为 例如，组蛋白翻译后修饰(PTM)塑造了人类细胞的局部染色质景观，以 在基因组中建立允许和抑制区域，以协调DNA转录、复制和 修理。然而，关于细胞如何整合信号，我们仍然有很多不了解的地方 从内部和外部协调适当的基因表达。除了经典的信号通路之外 将新陈代谢与转录结合起来(例如，核受体、激酶)，染色质直接“感觉”新陈代谢 通过转化为组蛋白PTM的代谢物的可用性来确定状态。由于代谢失调 几乎是每种疾病的组成部分，了解这些改变的代谢途径如何影响表观遗传学 监管和反之亦然，对于开发新的有效的疾病干预措施至关重要。然而， 代谢途径和染色质PTM信号的令人难以置信的复杂性和动态性质使其 很难描述代谢和染色质之间这种联系的分子水平的细节。来解决这个问题 问题是，我的实验室正在创造新的化学工具来确定组蛋白PTM的特定子集是如何被称为 酰化反应受酰基-辅酶A代谢的调节，以及这些PTM如何对基因产生特定的影响 表情。我们正在开发酰基辅酶A生物传感器，以确定酰基辅酶A的动态变化如何响应 对细胞条件和酰基辅酶A代谢如何发生区隔的影响，特别是关于 核间隔区和组蛋白酰化。此外，我们的生物传感器也将同样扩展我们的 了解乙酰辅酶A在正常和疾病条件下的代谢，将使 确定调节特定组蛋白酰化的酰基辅酶A产生酶和酰基转移酶。 为了确定组蛋白酰化如何影响基因表达，我们正在开发基于亲和力的探针来识别 与组蛋白酰化结合的蛋白质。通过鉴定这些结合蛋白，我们将能够指定特定的 这些PTM具有基因调控功能。有了这些信息，我们将能够开发出新的治疗方法 在酰基辅酶A和组蛋白上拦截代谢和基因组之间的通讯的策略 酰化水平，以准确地重新编程这些信号通路在疾病中。

Abstract Research over the last decades has uncovered epigenetic mechanisms that precisely regulate the genome. For instance, histone post-translational modifications (PTMs) shape the local chromatin landscape of human cells to establish permissive and repressive regions within the genome to orchestrate DNA transcription, replication, and repair. Nevertheless, there is still a great deal that we do not understand about how the cell integrates signals from inside and outside itself to coordinate proper gene expression. In addition to the classic signaling pathways that couple metabolism to transcription (e.g., nuclear receptors, kinases), chromatin directly “senses” metabolic status through the availability of metabolites that are converted to histone PTMs. Since metabolic dysregulation is a component of nearly every disease, understanding how these altered metabolic pathways impact epigenetic regulation and vice versa is critical for developing new and effective disease interventions. However, the incredible complexity and dynamic nature of metabolic pathways and chromatin PTM signaling has made it difficult to characterize the molecular-level details of this link between metabolism and chromatin. To tackle this problem, my lab is creating novel chemical tools to determine how a particular subset of histone PTMs called acylations are regulated by acyl-CoA metabolism and how these PTMs lead to specific effects on gene expression. We are developing acyl-CoA biosensors to determine how acyl-CoA dynamics change in response to cellular conditions and how compartmentalization of acyl-CoA metabolism occurs, particularly with respect to the nuclear compartment and histone acylation. Moreover, our biosensors will similarly expand our understanding of acyl-CoA metabolism under both normal and disease conditions and will enable the identification of the acyl-CoA-producing enzymes and acyltransferases that regulate specific histone acylations. To determine how histone acylations impact gene expression, we are developing affinity-based probes to identify proteins that bind to histone acylations. By identifying these binding proteins, we will be able to assign specific gene regulatory functions to these PTMs. With this information, we will be able to develop new therapeutic strategies to intercept communication between metabolism and the genome at the acyl-CoA and histone acylation levels to precisely reprogram these signaling pathways in disease.