Role of Kdm6a in escape from X inactivation and in cognition

 描述(由申请人提供)：在这项提案中，我讨论了组蛋白去甲基酶KDM6A在神经元分化过程中调节性二态基因表达的作用。KDM6A从染色质中去除一个抑制性组蛋白标记(H3K27me3)，从而导致基因激活。KDM6A是由一个逃避X失活的基因编码的，导致女性更高的表达。许多行为和精神表型受到异常表观遗传修饰的影响。其中一些表型以性别特有的方式表现出来，例如抑郁症在女性中更常见。我们观察到Kdm6a在脑亚区的表达存在性别差异，这使得该基因成为在差异基因调控中发挥作用的有吸引力的候选基因。此外，在歌舞伎综合征患者中发现了KDM6A突变和缺失，其特征是多种异常，包括轻度到严重的智能障碍，这表明KDM6A在正常发育中发挥着重要作用。为了研究KDM6A在性别特异性基因表达控制中的作用，我将重点研究早期神经元分化，使用来自我最近构建的一个新的小鼠模型的雄性和雌性ES细胞，以分析等位基因特异的基因表达和染色质结构。在神经元分化过程中，将监测KDM6A缺失的ES细胞的变化，以测量KDM6A缺失对神经元形态以及对染色质标记的建立和/或维持的影响。此外，我还将建立KDM6A在ES细胞及其神经元衍生细胞中的占位情况。将对男性和女性细胞中的基因表达进行测量，以寻找女性与男性KDM6A水平较高可能导致的性别差异。这项研究为研究性二型性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KDM6A在诱导性二态中的功能，从而调节神经细胞分化和发育中的基因表达。

 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.