Epigenetic regulation of alcohol tolerance and dependence by methyl CpG binding protein 2
甲基 CpG 结合蛋白 2 对酒精耐受性和依赖性的表观遗传调控
基本信息
- 批准号:9133075
- 负责人:
- 金额:$ 36.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-06-01 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAlcohol abuseAlcohol consumptionAlcohol dependenceAlcoholsAutomobile DrivingBindingBinding ProteinsBirdsBrainBrain regionChromatinChronicComplexDNADependenceDevelopmentDown-RegulationEngineeringEthanolExhibitsExperimental DesignsGene ExpressionGene TargetingGenesGenetic TranscriptionHeavy DrinkingImpaired cognitionLeadLiteratureMeasuresMediatingMethyl-CpG-Binding Protein 2MolecularMolecular ProfilingMusMutant Strains MicePathologicPhenotypePhosphorylationRecording of previous eventsRecruitment ActivityRegulationRegulator GenesRegulonRelapseRett SyndromeRoleSiteSubstance AddictionSystems BiologyTestingTranscription Repressor/CorepressorTreatment EfficacyValidationViral Vectoralcohol effectalcohol exposurealcohol use disorderanxiety-like behaviordifferential expressiondrinkingepigenetic regulationfollow-upgene repressiongenetic signaturegenome-wideinnovationmolecular domainmutantnew therapeutic targetnovelnovel therapeuticsprogramsreconstructionsedativesocialtherapeutic targetvalidation studiesvapor
项目摘要
Summary
Long-term alterations in gene expression programs are believed to be key to the development and
progression of alcohol use disorder (AUD). The methyl CpG binding protein 2 (MeCP2), the causative gene of
Rett syndrome, is a protein that binds methylated DNA and, in turn, recruits transcriptional repressors resulting
in persistent down-regulation of gene expression. We observed that MeCP2 mutant mice with reduced
capacity to recruit transcriptional repressors exhibit a robust alcohol–related phenotype characterized by
heightened sensitivity to the sedative effects of alcohol, reduced alcohol intake in limited access 2-bottle choice
and lack of escalation of drinking after passive induction of dependence.
Recent evidence indicates that MeCP2's primary function is to recruit a transcriptional repressor
complex at sites of methylated DNA through a discrete molecular domain. Importantly, MeCP2 has been found
to regulate a specific set of genes – or regulon – rather than broadly affecting gene expression levels, and we
found significant overlap between alcohol-regulated and MeCP2-regulated genes. Thus, in the present project
we will test the overarching hypothesis that MeCP2-regulated genes are key to alcohol's effects and to the
transition to escalated alcohol drinking in the setting of alcohol dependence. To test the sub-hypothesis that
recruitment of transcriptional repressors by MeCP2 is central to its effects on drinking, we will use MeCP2
mutant mice with reduced capacity to recruit transcriptional repressors in comparison with recently introduced
MeCP2 mutant mice with increased capacity to recruit transcriptional repressors, to provide optimal
perturbation of MeCP2 function for the analysis of MeCP2 regulated gene networks. To test the sub-hypothesis
that specific MeCP2 target genes and modulators are key to the transition to escalated drinking associated
with alcohol dependence, we will use a state of the art systems biology strategy that we recently validated for
the reconstruction and interrogation of genome-wide transcriptional interactomes from brain gene expression
profiles. This approach is centered on unbiased identification of transcriptional regulatory relationships from the
gene expression effects of the perturbations under study, rather than what is known from the literature or under
different sets of perturbations. Rather than identifying long lists of differentially expressed genes, this systems
biology strategy identifies and ranks a small number of genes driving the gene signatures associated with the
phenotype. Thus, specific mechanistic hypotheses on the role of MeCP2 in the effects of alcohol are obtained,
and will then be experimentally validated in paradigms of dependent and non-dependent alcohol drinking.
Ultimately, the results of this study will advance our understanding of the molecular mechanisms behind
excessive alcohol drinking in the setting of dependence and will lay the rationale for the exploitation of specific
MeCP2-regulated genes and modulators for the development of novel therapeutic concepts for AUD.
概括
人们认为,基因表达计划的长期变化是发展和
酒精使用障碍的进展(AUD)。甲基CpG结合蛋白2(MECP2),这是一种致病基因
RETT综合征是一种结合甲基化DNA的蛋白质,然后募集导致的转录表示
在基因表达的持续下调。我们观察到MECP2突变小鼠的减少
招募转录表示的能力暴露了以鲁棒性相关的表型为特征
对酒精的镇静作用的敏感性提高,在有限的2瓶选择中降低酒精摄入量
并缺乏通过依赖诱导后饮酒的升级。
最近的证据表明,MECP2的主要功能是招募转录代表
通过离散的分子结构域在甲基化DNA的位点复合物。重要的是,已经发现MECP2
调节一组特定的基因或调节子,而不是广泛影响基因表达水平,我们
发现酒精调节和MECP2调节的基因之间存在显着重叠。在当前的项目中
我们将测试总体假设,即MECP2调节的基因是酒精作用和对酒精作用的关键。
在酒精依赖的情况下过渡到升级的酒精饮酒。测试亚物种
MECP2招募转录表示对饮酒的影响至关重要,我们将使用MECP2
与最近引入的相比,与募集转录表示能力降低的突变小鼠
MECP2突变小鼠具有增加募集转录复制品的能力,以提供最佳
MECP2功能的扰动用于分析MECP2调控基因网络。测试子司假设
特定的MECP2靶基因和调节剂是过渡到升级饮酒的关键
借助酒精依赖,我们将使用最近验证的最先进的系统生物学策略
来自脑基因表达的全基因组转录相互作用的重建和询问
概况。这种方法集中在对转录调节关系的公正识别。
正在研究的扰动的基因表达效应,而不是文献中已知或以下的知识
不同的扰动集。该系统没有识别出不同表达的基因的列表
生物学策略识别并排名少数驱动与该基因的基因的基因
表型。这是关于MECP2在酒精作用中的作用的特定机械假设,
然后将在依赖和非依赖性饮酒的范式中对实验验证。
最终,这项研究的结果将提高我们对背后分子机制的理解
在依赖性的情况下过量饮酒,并将为开发特定的理由提供理由
MECP2调节的基因和调节剂,用于开发新的AUD治疗概念。
项目成果
期刊论文数量(0)
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