Targeting the host metabolome to reverse drug-induced epigenetic changes

项目摘要 病理性物质使用障碍是一组破坏性的精神疾病，其特征是 不断升级和失控的药物摄入以及经常持续的戒断和复发循环。之一 物质使用障碍转化研究的关键问题是， 导致动机行为模式的持续失调。染色质的长期变化 结构是物质使用中基因表达和行为持续失调的基础 紊乱染色质结构的调节需要整合来自染色体的无数信号。 环境，并且有大量文献表明，关键代谢物和辅因子的水平 调节染色质动力学。值得注意的是，几乎所有修饰组蛋白或DNA的酶都利用关键代谢物 作为其催化活性的底物或辅因子。因此，关键代谢物的可用性直接影响 细胞改变染色质结构的能力。我们的初步研究表明反复接触毒品 滥用会显著改变血清和大脑代谢组。许多失调的代谢物是那些 已知是表观遗传书写器和橡皮擦功能的关键辅助因子。与此同时， 在调节细胞代谢的细胞核中， 戒断总之，这些数据确定代谢组作为一种新的手段，目标表观遗传 物质使用障碍的监管。初始研究将利用药物自我给药和恢复 结合血清和脑代谢组学，进一步鉴定与药物摄入相关的代谢物， 药物寻求随后的研究将确定代谢信号的操纵如何改变行为 反应和大脑表观遗传学。通过饮食限制或 补充将阐明这些代谢物对行为的作用，以及细胞特异性基因操纵。 关键代谢酶将增加观察到的效应的特异性和清晰度。代谢操纵将是 再加上细胞特异性染色质分析，通过ATAC测序，定量质谱，以确定 组蛋白修饰和染色质相关蛋白复合物的变化，以检查 行为和表观遗传效应的相互作用。最后，我们将利用尖端的转基因小鼠， 在表观遗传写入器/擦除器中的关键代谢物结合位点产生可诱导点突变的技术， 评估当酶-代谢物相互作用被阻止时对行为和染色质结构的影响。 这些研究将定义一个新的研究领域，目标是物质使用中染色质的代谢调节 疾病并将确定新的转化研究目标，这将显着增加我们对疾病的了解 物质使用障碍的表观遗传调节

Project Summary Pathological substance use disorders are a set of devastating psychiatric conditions marked by a pattern of escalating and out of control drug intake and an often-persistent cycle of withdrawal and relapse. One of the critical questions for translational research on substance use disorders is how exposure to drugs of abuse leads to such persistent dysregulation in patterns of motivated behaviors. Long-lasting changes to chromatin structure underlie the persistent dysregulation of gene expression and behavior seen in substance use disorders. Regulation of chromatin structure requires the integration of a myriad of signals from the environment, and there is a robust literature demonstrating that levels of key metabolites and cofactors regulate chromatin dynamics. Notably, nearly all enzymes that modify histones or DNA utilize key metabolites as substrates or cofactors in their catalytic activity. Therefore, availability of key metabolites directly affects the ability of a cell to make alter chromatin structure. Our preliminary studies show that repeated exposure to drugs of abuse markedly alters the serum and brain metabolome. Many of the dysregulated metabolites are those known to be critical cofactors for the function of epigenetic writers and erasers. Parallel to this, genes involved in the regulation of cellular metabolism in the nucleus accumbens were markedly altered even after prolonged withdrawal. Taken together, these data identify the metabolome as a novel means to target epigenetic regulation in substance use disorders. Initial studies will utilize drug self-administration and reinstatement coupled with serum and brain metabolomics to further identify metabolites that correlate with drug intake and drug seeking. Subsequent studies will determine how manipulations of metabolite signaling alter behavioral response and brain epigenetics. Systemic manipulation of metabolites via dietary restriction or supplementation will clarify the role of these metabolites on behavior, and cell-specific gene manipulations of key metabolic enzymes will add specificity and clarity to observed effects. Metabolic manipulations will be coupled with cell-specific chromatin profiling via ATAC-sequencing, quantitative mass spectrometry to identify changes in histone modifications, and chromatin-associated protein complexes in order to examine the interaction of behavioral and epigenetic effects. Finally, we will utilize cutting edge transgenic mouse technology to create inducible point mutations in epigenetic writers/erasers at key metabolite binding sites to assess the effects on behavior and chromatin structure when enzyme-metabolite interactions are prevented. These studies will define a new field of research targeting metabolic regulation of chromatin in substance use disorders and will identify novel translational research targets that will markedly increase our understanding of epigenetic regulation in substance use disorders.