Role of Kdm6a in escape from X inactivation and in cognition

Kdm6a 在逃避 X 失活和认知中的作用

• 批准号: 8968769
• 负责人: JOEL Bradford BERLETCH
• 金额: $ 7.73万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8968769
• 关键词: Address; Alleles; Behavior; Behavioral; Binding; Biological Assay; Brain; Brain region; Cell Differentiation process; Cells; Chromatin; Chromatin Structure; Chromosomes; Cognition; Deletion Mutation; Development; Embryo; Epigenetic Process; Exhibits; Female; Future; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Proteins; Gene Silencing; Genes; Histone H3; Histones; Hybrids; Individual; Intellectual functioning disability; Kabuki Make-Up Syndrome; Knock-out; Lead; Lysine; Maintenance; Measurement; Measures; Mediating; Mental Depression; Methylation; Modification; Molecular; Monitor; Morphology; Neural Tube Defects; Neurologic; Neuronal Differentiation; Neurons; Patients; Phenotype; Play; Protein Binding; Regulation; Research; Role; Sex Characteristics; X Chromosome; X Inactivation; base; chromatin immunoprecipitation; cognitive testing; demethylation; embryonic stem cell; epigenetic regulation; follow-up; histone demethylase; in vivo; male; mouse model; neuron development; novel; public health relevance; research study; sex; sexual dimorphism; stem cell differentiation; transcriptome sequencing

 DESCRIPTION (provided by applicant): In this proposal, I address the role of the histone demethylase KDM6A in the regulation of sexually dimorphic gene expression during neuronal differentiation. KDM6A removes a repressive histone mark (H3K27me3) from chromatin, which results in gene activation. KDM6A is encoded by a gene that escapes X inactivation, resulting in higher expression in females. Many behavioral and psychiatric phenotypes are influenced by aberrant epigenetic modifications. Some of these phenotypes manifest in a sex-specific manner, for example depression is more common in females. The sex-specific differences we observed in Kdm6a expression in brain sub-regions make this gene an attractive candidate for a role in differential gene regulation. Furthermore, KDM6A mutations and deletions have been identified in Kabuki syndrome patients characterized by multiple anomalies including mild to severe intellectual disability, suggesting that KDM6A plays an important role in normal development. To investigate the role of KDM6A in the sex-specific control of gene expression I will focus on early neuronal differentiation using male and female ES cells derived from a novel mouse model I have recently constructed to assay allele-specific gene expression and chromatin structure. Changes in ES cells depleted of KDM6A will be monitored during neuronal differentiation to measure the effects of KDM6A depletion on neuron morphology and on the establishment and/or maintenance of chromatin marks. In addition, I will establish profiles of KDM6A occupancy in ES cells, and their neuronal derivatives. Measurements of gene expression in male and female cells will be done to look for sex-specific differences that may result from the higher levels of KDM6A in females versus males. This study represents a new avenue of research into molecular mechanisms of sexual dimorphisms. It will help to appreciate the role of histone demethylation in neurological gene regulation and will help clarify the function of KDM6A in eliciting sexual dimorphisms for the regulation of gene expression in neuronal cell differentiation and development.

 描述（由申请人提供）：在本提案中，我解决了组蛋白去甲基化酶KDM 6A在神经元分化过程中调节性二态基因表达的作用。KDM 6A从染色质中去除抑制性组蛋白标记（H3 K27 me 3），这导致基因激活。KDM 6A是由一个逃避X失活的基因编码的，导致女性中的表达更高。许多行为和精神表型受到异常表观遗传修饰的影响。其中一些表型表现为性别特异性的方式，例如抑郁症在女性中更常见。性别特异性差异，我们观察到Kdm 6a在大脑亚区域的表达，使这个基因在差异基因调控的作用有吸引力的候选人。此外，KDM 6A突变和缺失已在Kabuki综合征患者中鉴定，其特征在于多种异常，包括轻度至重度智力残疾，表明KDM 6A在正常发育中起重要作用。为了研究KDM 6A在性别特异性控制基因表达中的作用，我将使用来自我最近构建的一种新小鼠模型的雄性和雌性ES细胞来研究早期神经元分化，以测定等位基因特异性基因表达和染色质结构。在神经元分化期间监测耗尽KDM 6A的ES细胞的变化，以测量KDM 6A耗尽对神经元形态和对染色质标记的建立和/或维持的影响。此外，我将建立档案KDM 6A占用ES细胞，和他们的神经元衍生物。将进行雄性和雌性细胞中基因表达的测量，以寻找可能由雌性与雄性相比KDM 6A水平更高导致的性别特异性差异。这项研究为研究两性异形的分子机制开辟了一条新的途径。这将有助于理解组蛋白去甲基化在神经基因调控中的作用，并有助于阐明KDM 6A在神经细胞分化和发育中诱导性二态性以调控基因表达的功能。