Role of UTX in escape from X inactivation

描述(由申请人提供)： 表观遗传变化可通过DNA甲基化和染色质修饰等多种机制影响基因表达。特别是，组蛋白可能会受到与基因转录增加或减少相关的许多变化的影响。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，例如在X染色体失活的情况下。性别(男性，XY；女性，XX)之间的根本遗传差异导致了剂量补偿机制的必要性：在两性中，活跃的X染色体上调，在女性中，X染色体失活。虽然非活性X(Xi)上的大多数基因是沉默的，但一些基因已经获得了导致它们逃逸和随后从xi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脱X失活的基因的重要性。X失活与抑制性组蛋白标志相关，包括组蛋白H3上赖氨酸27的甲基化。我们认为，组蛋白去甲基酶UTX和JMJD3去除这种抑制性的组蛋白修饰是逃避X失活的重要部分。我们将追求以下三个目标：目标1.确定组蛋白H3K27去甲基酶是否参与了在发育早期通过H3K27去甲基化启动X失活逃逸；AIM2。确定组蛋白H3K27去甲基酶耗竭是否改变X失活逃逸的开始和维持；鉴定在分化过程中与UTX结合或相关的蛋白，这些蛋白可能有助于逃避X失活。我们的研究将有助于确定组蛋白去甲基酶在X染色体和整个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的表观遗传失调有关。

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.