Role of UTX in escape from X inactivation

UTX 在逃避 X 失活中的作用

• 批准号: 7807055
• 负责人: JOEL Bradford BERLETCH
• 金额: $ 2.1万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-15 至 2010-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7807055
• 关键词: ARID Domain; Aberrant DNA Methylation; Adult; Affect; Age; Binding; Biological Assay; Cells; Chromosomes; Complex; DNA Methylation; Defect; Development; Disease; Dosage Compensation (Genetics); Embryo; Enzymes; Epigenetic Process; Evolution; Excision; Female; Fibroblasts; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genetic; Genetic Transcription; Genome; Histones; Individual; Lead; Lysine; Maintenance; Malignant Neoplasms; Mass Spectrum Analysis; Methylation; Methyltransferase; Mus; Patients; Play; Process; Protein Binding; Proteins; RNA Interference; Regulation; Role; Tertiary Protein Structure; Time; Tissues; Turner' s Syndrome; Up-Regulation; X Chromosome; X Inactivation; Y Chromosome; base; chromatin modification; chromatin remodeling; demethylation; embryonic stem cell; histone modification; male; pluripotency; protein complex; protein purification; research study; sex; tumorigenesis

DESCRIPTION (provided by applicant): Epigenetic changes can influence gene expression through various mechanisms including DNA methylation and chromatin modifications. In particular, histones can be subject to many alterations associated with an increase or a decrease in gene transcription. Epigenetic regulation modifies individual genes but it can also affect a whole chromosome, for example in the case of X chromosome inactivation. The fundamental genetic difference between the sexes (male, XY; female, XX) has led to the necessity of dosage compensation mechanisms: up-regulation of the active X chromosome in both sexes and inactivation of an X chromosome in females. Although most genes on the inactive X (Xi) are silenced, some have attained mechanisms that lead to their escape and subsequent expression from the Xi. The importance of genes that escape X inactivation is illustrated by the phenotypic defects found in patients with Turner syndrome associated with a single X chromosome. X inactivation is associated with repressive histone marks including methylation of lysine 27 at histone H3. We proposethat removal of this repressive histone modification by the histone de-methylases UTX and JMJD3 is an essential part of escape from X inactivation. We will pursue the following three aims: Aim1. To determine whether histone H3K27 demethylases are involved in initiation of escape from X inactivation during early development through demethylation of H3K27; Aim2. To determine whether histone H3K27 demethylase depletion alters the onset and maintenance of escape from X inactivation; Aim3. To identify proteins bound to or associated with UTX during differentiation that may aide in escape from X inactivation. Our studies will help identify the role of histone demethylases in epigenetic regulation of the X chromosome and of the genome in general. Our studies are relevant to the understanding of epigenetic dysregulation in diseases such as cancer and aging.

描述（由申请人提供）： 表观遗传变化可以通过多种机制影响基因表达，包括DNA甲基化和染色质修饰。特别地，组蛋白可以经受与基因转录的增加或减少相关的许多改变。表观遗传调控可以改变单个基因，但也可以影响整个染色体，例如X染色体失活。性别（男性，XY;女性，XX）之间的基本遗传差异导致剂量补偿机制的必要性：两种性别中活性X染色体的上调和女性中X染色体的失活。虽然大多数在失活X（Xi）上的基因是沉默的，但有些基因已经获得了导致它们从Xi逃逸并随后表达的机制。在特纳综合征患者中发现的与单个X染色体相关的表型缺陷说明了逃避X失活的基因的重要性。X失活与抑制性组蛋白标记相关，包括组蛋白H3处赖氨酸27的甲基化。我们提出，通过组蛋白去甲基化酶UTX和JMJD 3去除这种抑制性组蛋白修饰是逃避X失活的重要组成部分。我们将追求以下三个目标：目标1。确定组蛋白H3 K27去甲基化酶是否参与了早期发育过程中通过H3 K27去甲基化逃避X失活的启动; Aim 2。确定组蛋白H3 K27去甲基化酶缺失是否改变了X失活逃逸的发生和维持; Aim 3.鉴定分化过程中与UTX结合或相关的蛋白质，这些蛋白质可能有助于逃避X失活。我们的研究将有助于确定组蛋白去甲基化酶在X染色体和基因组的表观遗传调控中的作用。我们的研究与理解癌症和衰老等疾病中的表观遗传失调有关。