The Epigenome in Substance Abuse Disorders: Engineering New Tools to Dissect Function from Form

许多研究将表观基因组变化与药物滥用障碍联系起来。但有一个 这是我们理解表观基因组机制作用的关键障碍。虽然表观基因组 修饰已被广泛绘制，并与基因表达和细胞内的变化相关。 表型，相关性不证明功能或因果关系。这一障碍的出现是因为 广泛使用的技术来扰乱表观基因组，包括药理学抑制和遗传学抑制。 敲除或过度表达，具有多效性效应。因此，尚不清楚表观基因组是否 修饰驱动基因状态的变化，是基因状态变化的结果，或者仅仅与基因状态变化相关。两 由此产生了重要的推论：1）尚不清楚是否以及哪些表观基因组修饰 驱动基因表达的变化，以及2）表观基因组修饰的时间稳定性， 会导致真正持久的“表观遗传”特性是未知的。提出的假设 表观基因组代表了一个位于基因组之上的强大调控系统， 通过设计新的工具来连接和控制这个系统，我们可以利用它 了解和解决药物滥用障碍的独特属性。一个指导目标是解剖 表观基因组修饰的功能，从它们的形式，并证明其特定的相关性， 物质滥用障碍为了实现这一目标，我们将开发工具来感知和诱导 表观基因组，并在反映人类遗传学，表观遗传学和 physiology.

Many studies have connected epigenomic changes to substance abuse disorders. However, there is a key barrier to our understanding of the epigenome’s mechanistic roles. While epigenomic modifications have been widely mapped and correlated with changes in gene expression and cellular phenotypes, correlation does not demonstrate function or causation. This barrier arises because widely used techniques to perturb the epigenome, including pharmacological inhibition and genetic knock-outs or overexpressions, suffer from pleiotropic effects. Thus, it is unclear if epigenomic modifications drive, are a result of, or are simply associated with changes in gene states. Two important corollaries arise from this: 1) It is unclear whether and which epigenome modifications drive changes in gene expression, and 2) the temporal stability of epigenome modifications that would result in truly persistent “epigenetic” properties is unknown. The hypothesis of the proposed work is that the epigenome represents a powerful regulatory system layered on top of the genome, and by engineering new tools to interface with and control this system, we can harness its unique properties to understand and tackle substance abuse disorders. A guiding goal is to dissect the function of epigenome modifications from their form and demonstrate their specific relevance to substance abuse disorders. To achieve this, we will develop tools to sense and induce changes in the epigenome, and do so spatiotemporally in systems reflective of human genetics, epigenetics, and physiology.