Epigenetic Markers in Huntington's disease Brain

亨廷顿病大脑中的表观遗传标记

• 批准号: 9119217
• 负责人: RICHARD H MYERS
• 金额: $ 2.31万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9119217
• 关键词: Address; Age of Onset; Appearance; Biological Markers; Blood; Blood Cells; Blood specimen; Brain; CAG repeat; CD4 Positive T Lymphocytes; Cell Nucleus; Cerebral cortex; Cerebrum; Cessation of life; ChIP-seq; Chorea; Clinical Trials; Complement; Computing Methodologies; Corpus striatum structure; Data; Diagnosis; Diffuse; Disease; Disease Progression; Drug Evaluation; Epigenetic Process; Exons; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genome Mappings; Genomics; Glutamates; Goals; Hereditary Disease; Histone H3; Histones; Human; Huntington Disease; Impaired cognition; Investigation; Lymphocyte; Lysine; Maps; Measures; Memory Loss; Messenger RNA; Methods; Methylation; Modeling; Molecular; Molecular Target; Movement; Mutation; Neurodegenerative Disorders; Neurons; Nuclear Inclusion; Outcome Study; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Prefrontal Cortex; Process; Research; Resources; Role; SNP genotyping; Sampling; Signal Transduction; Site; Sorting - Cell Movement; Staging; Synapses; System; Techniques; Technology; Tissues; Transcription Initiation Site; Trinucleotide Repeat Expansion; Ubiquitin; brain cell; cognitive skill; comparative; density; disorder control; epigenetic marker; excitotoxicity; gain of function; genome wide association study; genome-wide; genome-wide analysis; histone methylation; histone modification; human Huntingtin protein; insight; methylation biomarker; methylome; mind control; multicatalytic endopeptidase complex; mutant; neuron loss; novel; promoter; transmission process; Address; Age of Onset; Appearance; Biological Markers; Blood; Blood Cells; Blood specimen; Brain; CAG repeat; CD4 Positive T Lymphocytes; Cell Nucleus; Cerebral cortex; Cerebrum; Cessation of life; ChIP-seq; Chorea; Clinical Trials; Complement; Computing Methodologies; Corpus striatum structure; Data; Diagnosis; Diffuse; Disease; Disease Progression; Drug Evaluation; Epigenetic Process; Exons; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genome Mappings; Genomics; Glutamates; Goals; Hereditary Disease; Histone H3; Histones; Human; Huntington Disease; Impaired cognition; Investigation; Lymphocyte; Lysine; Maps; Measures; Memory Loss; Messenger RNA; Methods; Methylation; Modeling; Molecular; Molecular Target; Movement; Mutation; Neurodegenerative Disorders; Neurons; Nuclear Inclusion; Outcome Study; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Prefrontal Cortex; Process; Research; Resources; Role; SNP genotyping; Sampling; Signal Transduction; Site; Sorting - Cell Movement; Staging; Synapses; System; Techniques; Technology; Tissues; Transcription Initiation Site; Trinucleotide Repeat Expansion; Ubiquitin; brain cell; cognitive skill; comparative; density; disorder control; epigenetic marker; excitotoxicity; gain of function; genome wide association study; genome-wide; genome-wide analysis; histone methylation; histone modification; human Huntingtin protein; insight; methylation biomarker; methylome; mind control; multicatalytic endopeptidase complex; mutant; neuron loss; novel; promoter; transmission process

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a fatal, autosomal dominant neurodegenerative disorder caused by an expanded CAG tract in the HD gene that results in gradual loss of memory, cognitive skills and normal movements. Multiple lines of research point to dysregulated transcription as a prevailing feature of HD pathology and suggest that altered histone modification by the mutant protein (Htt) may contribute to this process. However, thus far there has been no genome-wide analysis of histone modifications in human HD brain. The studies proposed here apply novel genomic technology to the search for epigenetic signatures in HD brains with the goal of gaining insight into HD pathogenesis. Our proposal capitalizes on two unique resources: (1) a novel FACS-ChIP-seq method which we will apply to establish and compare the methylomes of neurons from HD and control brains; and (2) a unique sample of HD brains, including a set matched for CAG repeat expansion (range 42-44 repeats) but onset ages differing by 30 years or more. The brains have been extensively neuropathologically characterized for degree of both striatal and cortical involvement. Since we found that histone H3 methylation markings in HD brains overlap highly with the signal in CD4+ cells, we are also comparing the altered epigenetic signature seen in HD brain to that in blood samples at varying stages of disease (presymptomatic, early and advanced HD) as this may offer a novel epigenetic biomarker in HD blood. Such biomarkers are of translational significance for the evaluation of drug treatments to realign the disrupted gene expression. We have preliminary data using the FACS-ChIP-Seq method in six HD prefrontal cortex samples and eleven normal controls, which provides tantalizing evidence for the significance of the proposed studies and demonstrates our capabilities to apply the techniques and to meaningfully interpret the findings. Our approach represents the most comprehensive analysis to date addressing the role of histone methylation in HD pathogenesis. Regardless of outcome, these studies will provide critical new insights into the molecular pathways of HD pathogenesis and may also uncover novel molecular targets for HD treatment. The high translational impact of this proposal is increased by our proposal to identify and characterize a unique histone methylation biomarker in HD blood cells. If successful, identification of such a biomarker will greatly facilitate clinical trials for novel HD therapies and offers a novel method to evaluate whether new drug treatments rectify disrupted gene expression.

描述（由申请人提供）：亨廷顿氏病（HD）是由HD基因中CAG扩展引起的致命，常染色体显性神经退行性疾病，导致记忆力，认知技能和正常运动逐渐丧失。多种研究指向转录失调的多种研究是HD病理的主要特征，并表明突变蛋白（HTT）改变组蛋白修饰可能有助于这一过程。但是，到目前为止，还没有对人类高清大脑中组蛋白修饰的全基因组分析。这里提出的研究将新型的基因组技术应用于HD大脑中的表观遗传学特征，目的是洞悉HD发病机理。我们的提案资本利用了两个独特的资源：（1）一种新颖的FACS-CHIP-seq方法，我们将应用该方法来建立和比较HD和Control Brains神经元的甲基元素； （2）HD大脑的独特样本，包括与CAG重复膨胀相匹配的集合（范围42-44重复），但发病年龄差异30年或更长时间。大脑在神经病理学上具有广泛的纹状体和皮质受累程度的特征。由于我们发现高清大脑中的组蛋白H3甲基化标记与CD4+细胞中的信号高度重叠，因此我们还将HD脑中看到的表观遗传学特征改变与疾病不同阶段的血液样本中的表观遗传学特征（Presymymbistomant和Advanced HD）中的变化，因为这可能会为HD血液中的新型表观遗传学生物标记物提供HD血液中的新型表观遗传学标志物。这种生物标志物对于评估药物治疗以重新调整破坏基因表达的评估具有转化意义。我们使用六个HD前额叶皮层样品和11个正常对照的FACS-CHIP-seq方法获得了初步数据，这为提出的研究的意义提供了诱人的证据，并证明了我们应用技术并有意义地解释发现的能力。 我们的方法代表了迄今为止最全面的分析，该分析解决了组蛋白甲基化在HD发病机理中的作用。无论结果如何，这些研究都将为HD发病机理的分子途径提供关键的新见解，并可能揭示用于HD治疗的新型分子靶标。我们的建议识别和表征HD血细胞中独特的组蛋白甲基化生物标志物的提议增加了该提案的高转化影响。如果成功，对这种生物标志物的识别将极大地促进新型HD疗法的临床试验，并提供了一种新型方法来评估新药物治疗是否纠正了基因表达的干扰。