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: 10614939
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614939
• 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; 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.

项目概要/摘要 哺乳动物 X 染色体失活是一种复杂的表观遗传机制，可确保近乎平衡的 男性（XY）和女性（XX）之间的基因表达水平。这种染色体范围的调控使得 X 是研究异染色质调控和结构的理想模型。 X失活影响了相当大的一部分 哺乳动物基因组的一部分，对于正常发育和正常寿命至关重要。确实，X像差 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对理解 X 的结构和调节做出贡献 研究性染色体异常的人类状况，同时采用新技术来推进 领域。 在这里，我考虑与原子核内不活跃 X 的物理结构和位置相关的挑战， 重点关注长非编码 RNA (lncRNA)。通过将蛋白质支架化为柔性复合物 lncRNA 已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未得到解答。我将检查顺式和反式角色 保守的X连锁lncRNA位点及其转录物在调节X结构和位置方面的作用 细胞核内的染色体。我们发现 Dxz4 塑造了非活性 X 的独特二分结构 顺式和 Firre 显然控制反式中不活跃的 X 位置和表观遗传特征。在此，我提议 引入新方法来操纵这些和其他 lncRNA 位点并重新定位特定的 X 染色体 细胞核内的区域。这将解决物理位置在相关方面的基本作用 异染色质的形成和维持。 女性逃避 X 失活和男性 Y 的存在导致细胞中的性别二态性 生理。组织内的细胞类型多样性广泛，但人们对其知之甚少；然而，小说令人兴奋的新 技术可以测量体内数万个单细胞的基因表达和染色质特征。 为了解决性别相关基因在细胞和有机体水平上的作用，我将建立一个体内图谱 雄性和雌性小鼠组织单细胞的等位基因特征。单细胞技术也将应用于 具有性染色体非整倍性的胎儿和成人的小鼠和人体组织以确定其影响 关于细胞类型。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角色 体内染色体的性别差异和性染色体紊乱。

项目成果

Multi-condition and multi-modal temporal profile inference during mouse embryonic development.

小鼠胚胎发育过程中的多条件和多模式时间剖面推断。

• 发表时间: 2024-03-04
• 作者: Zhang, Ran;Qiu, Chengxiang;Filippova, Gala;Li, Gang;Shendure, Jay;Vert, Jean;Deng, Xinxian;Disteche, Christine;Noble, William Stafford
• 通讯作者: Noble, William Stafford

Sex chromosome aneuploidies in 2020-The state of care and research in the world.

2020 年性染色体非整倍体 - 世界护理和研究状况。

• 发表时间: 2020
• 作者: Gravholt, Claus H;Tartaglia, Nicole;Disteche, Christine
• 通讯作者: Disteche, Christine

Cross-species imputation and comparison of single-cell transcriptomic profiles.

单细胞转录组谱的跨物种插补和比较。

• 发表时间: 2023-10-20
• 作者: Zhang R;Yang M;Schreiber J;O'Day DR;Turner JMA;Shendure J;Disteche CM;Deng X;Noble WS
• 通讯作者: Noble WS