Adolescent Binge Ethanol Dysregulation of H3K36me3 Leads to Cryptic Transcription and Lasting Memory Deficits

青少年暴饮乙醇 H3K36me3 失调导致隐性转录和持久记忆缺陷

基本信息

批准号：
10569496
负责人：
Emily Rose Brocato
金额：
$ 3.24万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
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：
2021-09-25 至 2023-05-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10569496
关键词：
Adolescence Adolescent Adult Affect Alcohol consumption Alcohols Animal Behavior Animals Attention Automobile Driving Behavior Behavioral Binding Bioinformatics Biological Assay Brain Candidate Disease Gene ChIP-seq Chromatin Cognitive Cognitive deficits Critical Thinking DNA-Directed RNA Polymerase Data Deposition Development Dose Enzyme-Linked Immunosorbent Assay Epigenetic Process Ethanol Exposure to Future Gene Expression Gene Expression Profile Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genomic Segment Genomics Goals Histones Investigation Knowledge Lead Length Lysine Male Adolescents Malignant Neoplasms Measures Mediating Memory Memory impairment Methylation Modeling Molecular Mus Nucleosomes Pathology Pharmacologic Substance Play Prefrontal Cortex Quantitative Reverse Transcriptase PCR Reporting Research Research Personnel Role Stimulus Techniques Time Tissue-Specific Gene Expression Tissues Training Transcript Transcriptional Regulation Untranslated RNA Viral Vector Visuospatial Water Writing adolescent alcohol exposure adolescent binge drinking alcohol exposure behavioral outcome chromatin immunoprecipitation chromatin remodeling cognitive change cohort differential expression epigenetic regulation epigenome gene product histone methylation histone methyltransferase indexing long term memory memory consolidation novel object recognition overexpression prevent promoter skill acquisition skills success transcriptome sequencing underage drinking

项目摘要

PROJECT SUMMARY The prefrontal cortex (PFC) undergoes significant changes during adolescence, and alcohol exposure during this time is particularly damaging. Consuming alcohol, especially in binges, has been shown to negatively impact the adolescent brain, resulting in brain structural changes and lasting deficits in attention, visuospatial skills, and memory. The underlying mechanisms of these deficits are largely unknown; however, histone epigenetic regulation of gene expression provides an attractive mechanism for driving long-term behavioral and cognitive changes following binge ethanol. Through interaction with environmental stimuli, such as alcohol, epigenetic alterations can determine downstream gene expression, which in turn affects behavioral outcomes. The proposed study will investigate whether histone epigenetic alterations are the mechanism behind the persistent memory deficits of adolescents exposed to binge levels of ethanol. Specifically, the study will focus on tri-methylated histone 3, lysine 36 (H3K36me3). H3K36me3 has been shown to be affected by adolescent binge ethanol, and also plays significant roles in transcription regulation and memory function. These functional roles may provide a mechanism for how dysregulation of H3K36me3 by adolescent binge ethanol could underlie long-term memory deficits. Additionally, H3K36me3 is an under-studied mark, and further investigation of its role in memory function and cryptic transcription will provide valuable data for others involved in behavioral epigenetic research. Through this proposal, we intend to determine how H3K36me3-regulated loci and gene expression patterns within the PFC are altered after adolescent binge ethanol. By overlaying chromatin immunoprecipitation (ChIP) sequencing with RNA sequencing data, we will determine how ethanol- induced dysregulation of H3K36me3 affects gene expression, and at which loci these changes are occurring. We also plan to manipulate H3K36me3 levels within the PFC to determine if altering this epigenetic mark can change the behavioral outcomes of adolescent binge ethanol. These studies therefore have the potential to expand the knowledge of how epigenetic alterations can induce lasting behavioral changes. The success of these epigenetic and genomic studies will identify novel genes that might contribute to the persistent memory deficits associated with adolescent binge ethanol, which could ultimately lead to pharmaceutical targets to reverse cognitive deficits associated with adolescent binge drinking. Additionally, this study will facilitate my training in molecular techniques, bioinformatics analyses, and animal behavior models. In addition to the critical thinking, scientific writing, and professional development skills that I will be trained in, this research will prepare me to become a successful independent researcher studying how environmental influences, such as alcohol consumption, is encoded into the epigenome and how this can cause lasting impacts to behavior.

项目概要前额皮质（PFC）在青春期发生显着变化，并且在酒精暴露期间这次的破坏性尤其大。饮酒，尤其是在暴饮暴食时，已被证明会产生负面影响影响青少年大脑，导致大脑结构变化和注意力、视觉空间的持久缺陷技能和记忆力。这些缺陷的根本机制在很大程度上尚不清楚；然而，组蛋白基因表达的表观遗传调控为驱动长期行为提供了一种有吸引力的机制以及酗酒后的认知变化。通过与环境刺激物（例如酒精）的相互作用，表观遗传改变可以决定下游基因表达，进而影响行为结果。拟议的研究将调查组蛋白表观遗传改变是否是其背后的机制接触过量乙醇的青少年会出现持续性记忆缺陷。具体来说，该研究将重点三甲基化组蛋白 3、赖氨酸 36 (H3K36me3)。 H3K36me3 已被证明受青少年影响狂饮乙醇，还在转录调节和记忆功能中发挥重要作用。这些功能性的角色可能提供了一种机制，解释青少年酗酒导致的 H3K36me3 失调如何发挥作用是长期记忆缺陷的根源。此外，H3K36me3 是一个尚未充分研究的标记，需要进一步调查它在记忆功能和神秘转录中的作用将为其他参与其中的人提供有价值的数据行为表观遗传学研究。通过这个提案，我们打算确定 H3K36me3 调控的位点青少年酗酒后，PFC 内的基因表达模式会发生改变。通过叠加染色质免疫沉淀 (ChIP) 测序与 RNA 测序数据，我们将确定乙醇如何- H3K36me3 诱导的失调会影响基因表达以及这些变化发生在哪些位点。我们还计划操纵 PFC 内的 H3K36me3 水平，以确定改变这种表观遗传标记是否可以改变青少年酗酒的行为结果。因此，这些研究有可能扩展关于表观遗传改变如何引起持久行为变化的知识。的成功这些表观遗传学和基因组研究将鉴定出可能有助于持久记忆的新基因与青少年酗酒相关的缺陷，这最终可能导致药物目标逆转与青少年酗酒相关的认知缺陷。此外，这项研究将有助于我分子技术、生物信息学分析和动物行为模型方面的培训。除了我将接受批判性思维、科学写作和专业发展技能的培训，这项研究将帮助我成为一名成功的独立研究员，研究环境如何影响，例如饮酒被编码到表观基因组中，以及这如何对行为产生持久影响。