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Neuron subtype specific role of DNA methylcytosine dioxygenase TET1 in cocaine addiction

DNA甲基胞嘧啶双加氧酶TET1在可卡因成瘾中的神经元亚型特异性作用

基本信息

批准号：
10431868
负责人：
Jian Feng
金额：
$ 34.09万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10431868
关键词：
Address Affect Behavior Behavioral Brain CRISPR/Cas technology Cells Chronic Cocaine Cocaine Dependence Coupled Cytosine DNA DNA Methylation DNA Modification Process DNA Sequence DNA methylation profiling Dinucleoside Phosphates Dioxygenases Dopamine Dopamine D2 Receptor Drug Addiction Economic Burden Enzymes Epigenetic Process Family Family member Future Gene Expression Gene Silencing Genes Genetic Transcription Genomic DNA Goals Health Human Interphase Cell Lead Literature Mediating Molecular Morphology Mus Neuronal Plasticity Neurons Neurophysiology - biologic function Nucleus Accumbens Oxides Pathway interactions Pattern Play Population Projection Positioning Attribute Process Protein translocation Reporting Resolution Rewards Role Site Stimulus Testing Therapeutic Time Validation Ventral Striatum Work addiction base brain reward regions brain tissue cell type conditional knockout demethylation drug reward epigenome editing member methyl group novel promoter response reward circuitry social whole genome

项目摘要

Neural function requires accurate control of gene transcription in response to environmental stimuli. Epigenetics plays a crucial role in this process by modulating gene expression without changing underlying DNA sequences. DNA methylation is a major epigenetic mechanism, wherein a methyl group is covalently coupled to the C5 position of cytosine, predominantly at 5'-CpG-3' dinucleotide sites. Though still few in number, accumulating evidence demonstrates that DNA methylation may play important roles in drug addiction. However, to firmly establish DNA methylation's role in drug addiction, the question of whether and how DNA methylation changes take place and function in neurons must be addressed. This is particularly true for those defined neuronal subtypes selectively engaged in drug addiction. To address this question, we herein propose to study methylcytosine dioxygenase TET1, a newly identified DNA demethylation enzyme, and its mediated DNA methylation turnover in the two major neuron types (D1- and D2- medium spiny neurons (MSNs)) in nucleus accumbens in cocaine addiction. In the past, we have found TET1, but not TET2 or TET3 (the other two members of the dioxygenase family), is selectively regulated by cocaine in the nucleus accumbens. We have also shown TET1 mediates drug reward behaviors. Here, we propose TET1 carries distinct functions in D1- and D2-MSNs, which usually play opposite roles in addiction reward circuitry. We will also elucidate TET1-mediated neuron subtype-specific DNA methylation changes in D1- and D2-MSNs. Lastly, we will probe the long-standing question of the causal functional role of DNA methylation in drug addiction-relevant behavior through a proven CRISPR-Cas9 based epigenome editing approach to modify DNA methylation at selective loci. Upon completion, our study will not only advance our scientific understanding of DNA epigenetic underpinnings of drug addiction in a neuron subtype-specific manner, it will also provide a path to manipulate behaviors associated with drug addiction through cell type- specific precision epigenome editing, which has obvious potential utility for future therapeutic applications.

神经功能需要精确控制基因转录以响应环境刺激。表观遗传学在这一过程中发挥着至关重要的作用，它可以调节基因表达而不改变潜在的基因表达。 DNA 序列。 DNA甲基化是一种主要的表观遗传机制，其中甲基以共价键连接与胞嘧啶的 C5 位置偶联，主要在 5'-CpG-3' 二核苷酸位点。虽然还是少数越来越多的证据表明 DNA 甲基化可能在药物中发挥重要作用瘾。然而，为了确定 DNA 甲基化在吸毒成瘾中的作用，是否和必须解决 DNA 甲基化变化如何发生以及神经元功能如何的问题。这一点特别对于那些选择性地参与毒瘾的定义的神经元亚型来说确实如此。为了解决这个问题，我们在此建议研究甲基胞嘧啶双加氧酶 TET1，这是一种新发现的 DNA 去甲基化酶酶及其介导的两种主要神经元类型（D1- 和 D2- 介质）中的 DNA 甲基化转换可卡因成瘾中伏隔核中的多刺神经元（MSN）。过去我们发现过TET1，但是不是 TET2 或 TET3（双加氧酶家族的其他两个成员），在伏隔核。我们还表明 TET1 介导药物奖赏行为。在此，我们建议 TET1 在 D1-和 D2-MSN 中具有不同的功能，它们通常在成瘾奖励中发挥相反的作用电路。我们还将阐明 D1- 中 TET1 介导的神经元亚型特异性 DNA 甲基化变化和 D2-MSN。最后，我们将探讨 DNA 因果功能作用这一长期存在的问题通过经过验证的基于 CRISPR-Cas9 的表观基因组编辑实现药物成瘾相关行为的甲基化在选择性基因座上修饰 DNA 甲基化的方法。完成后，我们的学习不仅会提高我们的对神经元亚型特异性药物成瘾的 DNA 表观遗传基础的科学理解以这种方式，它还将提供一条通过细胞类型操纵与毒瘾相关的行为的途径—— 特定的精确表观基因组编辑，对未来的治疗应用具有明显的潜在效用。