X chromosome regulation and role in aneuploidy

项目摘要/摘要 哺乳动物的X染色体失活是一种复杂的表观遗传机制，它确保了一种近平衡的 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节使 X是研究异染色质调节和结构的理想模型。X失活影响相当大的一部分 它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像差 与出生缺陷和与年龄相关的疾病有关。我的研究小组已经做出了几项 通过开发有用的小鼠模型和 研究性染色体异常的人类状况，同时拥抱新技术以推进 田野。 在这里，我考虑了与非活性X在原子核内的物理结构和位置有关的挑战， 重点是长的非编码RNA(LncRNAs)。通过将蛋白质支架到柔性复合体lncRNAs 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 关于他们的行动机制，问题仍然没有得到回答。我将研究顺式和跨式角色 保守的X连锁LncRNA基因座及其转录本对X的结构和位置的调控 细胞核内的染色体。我们发现Dxz4形成了非活性X的独特的二元组结构 顺式和Firre基因明显控制反式基因的非活性X定位和表观遗传特征。在此，我建议 引入新的方法来操纵这些和其他lncRNA基因座并重新定位特定的X染色体 核内的区域。本课程将阐述物理位置在以下方面的基本作用 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型性 生理学。组织内的细胞类型多样性是广泛的，但了解得很少；然而，新的令人兴奋的新的 技术可以在体内测量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生物水平上的作用，我将建立一个体内图谱 雄性和雌性小鼠组织中单个细胞的等位基因特征。单电池技术也将应用于 小鼠和人胎儿组织与成人性染色体非整倍体测定的影响 关于细胞类型。一种有趣的可能性是，对非整倍体的适应性发育表观遗传反应 解释表型变异。为了探索这一点，我将比较组织中的表观遗传学特征和获得的特征 在诱发X染色体丢失的同基因细胞系中。我的目标是了解性行为的作用 染色体中的性别差异和体内的性染色体异常。

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.