X chromosome regulation and role in aneuploidy

X 染色体调控及其在非整倍性中的作用

• 批准号: 10395506
• 负责人: Christine M. Disteche
• 金额: $ 70.68万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395506
• 关键词: Address; Adult; Affect; Alleles; Aneuploidy; Atlases; Biological Models; Cell Line; Cell Nucleus; Cell physiology; Cells; Chromatin; Chromosome abnormality; Chromosomes; Complex; Congenital Abnormality; Development; Disease; Elements; Ensure; Epigenetic Process; Female; Gene Dosage; Gene Expression; Genes; Genome; Goals; Heterochromatin; Human; Lead; Link; Location; Longevity; Maintenance; Measures; Modification; Mus; Normal tissue morphology; Phenotype; Physiology; Regulation; Research; Role; Scaffolding Protein; Sex Chromosome Disorders; Sex Chromosomes; Sex Differences; Shapes; Structure; Study models; Tissues; Transcript; Untranslated RNA; X Chromosome; X Inactivation; XY females; age related; cell type; chromosome X loss; flexibility; human fetus tissue; in vivo; male; mammalian genome; mouse model; new technology; novel; novel strategies; response; sex; sex chromosome aneuploidy; sexual dimorphism; single cell technology

Project Summary/Abstract Mammalian X chromosome inactivation is a complex epigenetic mechanism that ensures a near-balanced level of gene expression between males (XY) and females (XX). This chromosome-wide regulation makes the X an ideal model for studying heterochromatin regulation and structure. X inactivation affects a sizable portion of the mammalian genome and is crucial for normal development and normal lifespan. Indeed, X aberrations have been linked to birth defects and to age-related diseases. My research group has made several contributions to understanding the structure and regulation of the X by developing useful mouse models and studying human conditions with sex chromosome anomalies, while embracing novel technologies to advance the field. Here, I consider challenges related to the physical structure and location of the inactive X within the nucleus, with a focus on long non-coding RNAs (lncRNAs). By scaffolding proteins into flexible complexes lncRNAs have emerged as adaptable elements that organize chromatin and regulate gene expression, but many questions remain unanswered about their mechanisms of action. I will examine the cis- and trans- roles of conserved X-linked lncRNA loci and their transcripts in regulating the structure and location of the X chromosome within the nucleus. We found that Dxz4 shapes the unique bipartite structure of the inactive X in cis and Firre apparently controls the inactive X location and epigenetic features in trans. Here, I propose to introduce new approaches to manipulate these and other lncRNA loci and to relocate specific X chromosome regions within the nucleus. This will address the fundamental role of physical location in relation to heterochromatin formation and maintenance. Escape from X inactivation in females and the presence of a Y in males lead to sexual dimorphisms in cell physiology. Cell-type diversity within tissues is extensive but poorly understood; yet, novel exciting new technologies can measure gene expression and chromatin features in tens of thousands of single cells in vivo. To address the role of sex-linked genes at the cellular and organismal level I will establish an in vivo atlas of allelic features in single cells of male and female mouse tissues. Single-cell technology will also be applied to mouse and human tissues from fetuses and adults with sex chromosome aneuploidy to determine the impact on cell types. An interesting possibility is that an adaptive developmental epigenetic response to aneuploidy explains phenotypic variability. To explore this, I will compare epigenetic features in tissues to those obtained in isogenic cell lines with induced X chromosome loss. My goal is to understand the role of the sex chromosomes in sex differences and sex chromosome disorders in vivo.

项目总结/摘要 哺乳动物X染色体失活是一种复杂的表观遗传机制， 雄性（XY）和雌性（XX）之间的基因表达水平。这种染色体范围的调节使得 X是研究异染色质调控和结构的理想模型。X染色体失活影响了相当大的一部分 这是哺乳动物基因组的重要组成部分，对正常发育和正常寿命至关重要。事实上，X光畸变 与出生缺陷和年龄相关疾病有关。我的研究小组做了几个 通过开发有用的小鼠模型， 研究性染色体异常的人类状况，同时采用新技术， 外地 在这里，我考虑与核内不活跃X的物理结构和位置相关的挑战， 长链非编码RNA（lncRNA）。通过将蛋白质支架化成柔性复合物lncRNA 已经成为组织染色质和调节基因表达的适应性元件，但许多 关于其作用机制的问题仍然没有答案。我将研究 保守的X连锁lncRNA基因座及其转录物在调节X染色体的结构和位置中的作用 细胞核内的染色体。我们发现Dxz 4塑造了非活性X的独特二分结构， 顺式和Firre显然控制着非活性X的位置和反式中的表观遗传特征。 引入新方法来操纵这些和其它lncRNA基因座并重新定位特定的X染色体 核内的区域。这将解决物理位置在以下方面的基本作用： 异染色质形成和维持。 雌性逃避X染色体失活和雄性Y染色体的存在导致细胞的性二型 physiology.组织内的细胞类型多样性是广泛的，但知之甚少;然而，新的令人兴奋的新 技术可以测量体内数万个单细胞中的基因表达和染色质特征。 为了解决性连锁基因在细胞和生物体水平上的作用，我将建立一个体内图谱， 雄性和雌性小鼠组织的单细胞中的等位基因特征。单细胞技术也将应用于 小鼠和人类组织从胎儿和成人的性染色体非整倍体，以确定影响 细胞类型。一个有趣的可能性是，对非整倍体的适应性发育表观遗传反应 解释了表型变异为了探索这一点，我将比较组织中的表观遗传特征和获得的表观遗传特征。 在诱导X染色体丢失的同基因细胞系中。我的目标是了解性别的作用 性差异和体内性染色体疾病中的染色体。