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.

项目摘要/摘要 哺乳动物X染色体灭活是一种复杂的表观遗传机制，可确保几乎平衡 男性（XY）和女性（XX）之间的基因表达水平。这种整个染色体的调节使得 X研究异染色质调节和结构的理想模型。 x灭活会影响相当大的部分 哺乳动物的基因组的，对于正常发育和正常寿命至关重要。确实，x畸变 与先天缺陷和与年龄有关的疾病有联系。我的研究小组做了几个 通过开发有用的鼠标模型和 通过性染色体异常研究人类状况，同时拥抱新技术以推进 领域。 在这里，我考虑与核内无效X的物理结构和位置有关的挑战， 专注于长的非编码RNA（LNCRNA）。通过将蛋白质脚手架成柔性复合物lncrnas 已成为组织染色质和调节基因表达的适应性元素，但许多 关于他们的行动机制，问题仍然没有得到答复。我将研究 保守的X连锁LNCRNA基因座及其在调节X的结构和位置方面的转录本 细胞核内的染色体。我们发现DXZ4塑造了非活动X的独特双分裂结构 CI和FIRE显然控制着反式的X位置和表观遗传特征。在这里，我建议 引入新方法来操纵这些和其他lncRNA基因座并重新放置特定的X染色体 核内的区域。这将解决与物理位置有关的基本作用 异染色质形成和维护。 逃避女性的X失活和男性中A Y的存在导致细胞中的性二态性 生理。组织内的细胞类型多样性广泛，但知之甚少。然而，小说令人兴奋的新 技术可以在体内数万个单个细胞中测量基因表达和染色质特征。 为了解决性别连接基因在细胞和生物层的作用，我将建立一个体内地图 男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 来自胎儿和性染色体非整倍性的小鼠和人体组织，以确定影响 在细胞类型上。一个有趣的可能性是自适应发育表观遗传学对非整倍性的反应 解释表型变异性。为了探讨这一点，我将比较组织中的表观遗传特征与获得的表观遗传特征 在具有诱导的X染色体损失的同基因细胞系中。我的目标是了解性的角色 性别差异和性染色体疾病中的染色体。