lncRNA regulation of the HTT gene via a hominid-specific transposable element

lncRNA通过原始人类特异性转座元件调节HTT基因

• 批准号: 8783265
• 负责人: Shari Lenore Wiseman
• 金额: $ 1.85万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-07 至 2015-01-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783265
• 关键词: Advanced Development; Affect; Affinity Chromatography; Anxiety; Apoptosis; Autistic Disorder; Bacterial Artificial Chromosomes; Behavior; Behavioral; Binding; Bioinformatics; Biological Assay; Brain; Brain region; Cell Culture Techniques; Cell Death; Cells; Cerebellum; Chromatin; Cognitive; Complex; Corpus striatum structure; DNA; DNA Insertion Elements; DNA Sequence; DNA Transposable Elements; Data; Development; Disease model; Embryo; Emotional; Exhibits; Exons; Fibroblasts; Functional RNA; Gene Dosage; Gene Expression; Gene Expression Regulation; Gene Targeting; Generations; Genes; Genetic; Genetic Transcription; Genomic DNA; Histones; Hominidae; Human; Human Genome; Huntington Disease; Impairment; Inherited; Introns; Knock-out; Knockout Mice; Length; Light; Link; Mediating; Messenger RNA; Methylation; Modeling; Molecular; Motor; Mus; Nature; Neurodegenerative Disorders; Neurons; Pan Genus; Pathology; Pattern; Play; Process; Proteins; Recruitment Activity; Regulation; Regulator Genes; Regulatory Element; Relative (related person); Retrotransposon; Role; Symptoms; System; Testing; Transcript; Transgenes; Transgenic Mice; Transport Vesicles; Trinucleotide Repeats; Untranslated RNA; Up-Regulation; Vesicle; cell motility; chromatin remodeling; cognitive function; gain of function; human Huntingtin protein; improved; knock-down; mRNA Expression; morris water maze; mutant; novel; polyglutamine; public health relevance; reconstitution; research study

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a neurodegenerative disorder marked by debilitating motor, cognitive, and emotional symptoms. It is caused by a dominantly inherited CAG triplet repeat expansion in the Huntingtin (HTT) gene, which gives rise to HD pathology both via toxic gains of function of the mutant HTT protein and interference with the critical functions of wild-type HTT. This proposal seeks to better elucidate how the expression of the wild-type human HTT gene is regulated by a hominid-specific long noncoding RNA (lncRNA) that has been linked to autism, highlighting its potential importance in the brain. Preliminary data indicate that the lncRNA is expressed in the human brain in a similar regional enrichment pattern as HTT mRNA, and that it increases human HTT expression in transgenic mice expressing both human genes. Cell culture assays will investigate whether an intronic transposable element in the HTT gene is necessary and sufficient to confer its regulation by the lncRNA, and to identify the chromatin remodeling processes that are recruited by the lncRNA to increase HTT transcription. The human lncRNA and HTT genes will then be expressed in transgenic mice to reconstitute the genetic regulatory system. Experiments in these mice will examine the effects of lncRNA expression on molecular, cellular, and behavioral processes that are enhanced by wild-type HTT and impaired in HD models. Specifically, neuronal gene transcription, apoptosis, vesicle motility, anxiety-like behaviors, and cognitive function in the Morris water maze will be assayed. Illuminating this novel, hominid-specific mechanism controlling the expression of wild-type HTT will provide a more thorough understanding of the normal functions that HD pathology impinges upon, and may thereby advance the development of improved therapies.

描述（由申请人提供）：亨廷顿氏病（HD）是一种神经退行性疾病，以使运动，认知和情绪症状使人衰弱。它是由亨廷汀（HTT）基因中主要遗传的CAG三重态重复​​扩展引起的，这既可以通过突变HTT蛋白的功能的有毒功能以及干扰野生型HTT的关键功能来引起HD病理。该提议旨在更好地阐明野生型人类HTT基因的表达如何受到与自闭症有关的人类特异性长的非编码RNA（LNCRNA）的调节，这突出了其在大脑中的潜在重要性。初步数据表明，lncRNA以与HTT mRNA相似的区域富集模式在人脑中表达，并且它增加了表达这两个人类基因的转基因小鼠的人类HTT表达。细胞培养分析将研究HTT基因中的内含子旋转元件是否需要且足以通过lncRNA进行调节，并确定LNCRNA募集的染色质重塑过程以增加HTT转录。然后将在转基因小鼠中表达人lncRNA和HTT基因，以重建遗传调节系统。这些小鼠的实验将检查lncRNA表达对野生型HTT增强并在HD模型中受损的分子，细胞和行为过程的影响。具体而言，将分析神经元基因转录，凋亡，囊泡运动，焦虑样行为和莫里斯水迷宫中的认知功能。阐明控制野生型HTT表达的这种新颖的，人类特异性的机制将提供对HD病理影响的正常功能的更彻底的理解，从而可以推进改进的治疗方法的发展。