Eavesdropping on the conversation between chromatin and metabolism

窃听染色质和新陈代谢之间的对话

基本信息

批准号：
10622505
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
项目类别：
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

项目摘要

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。例如，组蛋白翻译后修饰 (PTM) 塑造人类细胞的局部染色质景观在基因组内建立许可和抑制区域来协调 DNA 转录、复制和然而，关于细胞如何整合信号，我们仍然有很多不了解的地方。除了经典的信号传导途径之外，还从内部和外部协调适当的基因表达。将代谢与转录结合起来（例如核受体、激酶），染色质直接“感知”代谢由于代谢失调，通过转化为组蛋白 PTM 的代谢物的可用性来确定状态。是几乎所有疾病的组成部分，了解这些代谢途径如何影响表观遗传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。代谢途径和染色质 PTM 信号传导令人难以置信的复杂性和动态性质使其成为可能很难在分子水平上描述新陈代谢和染色质之间联系的细节。问题，我的实验室正在创建新颖的化学工具来确定组蛋白 PTM 的特定子集如何称为酰化受酰基辅酶 A 代谢调节，以及这些 PTM 如何对基因产生特定影响我们正在开发酰基辅酶A生物传感器来确定酰基辅酶A动力学如何响应而变化。细胞条件以及酰基辅酶A代谢的区室化如何发生，特别是在此外，我们的生物传感器将同样扩展我们的能力。了解正常和疾病条件下酰基辅酶A的代谢，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通过识别这些结合蛋白，我们将能够指定特定的组蛋白酰化蛋白。有了这些信息，我们将能够开发新的疗法。拦截酰基辅酶A和组蛋白代谢与基因组之间通讯的策略酰化水平以精确地重新编程疾病中的这些信号通路。