Eavesdropping on the conversation between chromatin and metabolism

窃听染色质和新陈代谢之间的对话

• 批准号: 10277009
• 负责人: Katharine Diehl
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10277009
• 关键词: Acyl Coenzyme A; Acylation; Acyltransferase; Affinity; Binding Proteins; Biosensor; Cells; Chemicals; Chromatin; Communication; DNA; Disease; Enzymes; Epigenetic Process; Gene Expression; Genes; Genetic Transcription; Genome; Histones; Human; Intercept; Intervention; Lead; Link; Metabolic; Metabolic Pathway; Metabolism; Modification; Molecular; Nature; Nuclear; Nuclear Receptors; Phosphotransferases; Post-Translational Protein Processing; Proteins; Regulator Genes; Research; Shapes; Signal Pathway; Signal Transduction; base; combat; epigenetic regulation; novel; novel therapeutic intervention; repaired; response; tool

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.

摘要 过去几十年的研究已经发现了精确调节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， 在基因组内建立允许和抑制区域，以协调DNA转录、复制和 修复.尽管如此，我们仍然不了解细胞如何整合信号 来协调基因的正常表达。除了经典的信号通路 将代谢与转录偶联（例如，核受体，激酶），染色质直接“感觉”代谢 通过代谢物转化为组蛋白PTM的可用性来确定状态。因为代谢失调 是几乎所有疾病的组成部分，了解这些改变的代谢途径如何影响表观遗传 监管和监管对制定新的有效疾病干预措施至关重要。但 代谢途径和染色质PTM信号传导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细节。解决这个 问题，我的实验室正在创造新的化学工具，以确定一个特定的组蛋白PTM子集如何被称为 酰化受酰基辅酶A代谢的调节，以及这些PTM如何对基因表达产生特异性影响。 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动力学如何响应 细胞条件以及酰基辅酶A代谢的区室化是如何发生的，特别是关于 核室和组蛋白酰化。此外，我们的生物传感器将同样扩大我们的 了解在正常和疾病条件下的酰基辅酶A代谢，并将使 鉴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是如何影响基因表达的，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。通过识别这些结合蛋白，我们将能够分配特定的 基因调控功能。有了这些信息，我们将能够开发新的治疗方法， 在酰基辅酶A和组蛋白上阻断代谢和基因组之间通讯的策略 酰化水平来精确地重新编程疾病中的这些信号通路。