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.

抽象的 在过去的几十年中，研究发现了精确调节基因组的表观遗传机制。为了 实例，组蛋白的翻译后修饰（PTMS）塑造了人类细胞的局部染色质景观 在基因组中建立允许和反射区域，以协调DNA转录，复制和 维修。但是，仍然有很多我们不了解细胞如何整合信号 从内部和外部自身来协调适当的基因表达。除了经典的信号通路 那对转录的新陈代谢（例如核接收器，激酶），染色质直接“感觉”代谢 通过转换为组蛋白PTM的代谢产物的可用性。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 监管，反之亦然对于制定新的有效疾病干预措施至关重要。但是， 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已使它成为现实 很难表征代谢和染色质之间这种联系的分子级细节。解决这个问题 问题，我的实验室正在创建新颖的化学工具，以确定特定组蛋白PTM的特定子集称为 酰基化由酰基-COA代谢调节，以及这些PTM如何对基因产生特定影响 表达。我们正在开发酰基-COA生物传感器，以确定酰基-COA动力学如何变化。 到细胞条件以及如何发生酰基-COA代谢的分区化，特别是相对于 核区室和组蛋白酰化。此外，我们的生物传感器也将同样扩展我们的 了解正常和疾病条件下酰基-COA代谢 鉴定酰基-COA产生的酶和调节特异性组蛋白酰基化的酰基转移酶。 为了确定组蛋白酰基化如何影响基因表达，我们正在开发基于亲和力的问题以识别 结合组蛋白酰基化的蛋白质。通过识别这些结合蛋白，我们将能够分配特定 这些PTM的基因调节功能。有了这些信息，我们将能够开发新的疗法 拦截代谢和基因组与酰基-COA和组蛋白之间的沟通的策略 酰基化水平以精确重新编程疾病中的这些信号通路。