Functional Analysis of Programmed Genome Rearrangement

程序化基因组重排的功能分析

• 批准号: 10093088
• 负责人: Jeramiah James Smith
• 金额: $ 37.04万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093088
• 关键词: Address; Anaphase; Biology; Cell Lineage; Chromatin; Chromosome Structures; DNA; DNA Methylation; DNA Sequence; Development; Epigenetic Process; Funding; Genes; Genome; Genome Stability; Germ Cells; Health; Heritability; Higher Order Chromatin Structure; Human; Human Biology; Human Genome; Individual; Instruction; Lampreys; Life; Light; Maintenance; Malignant Neoplasms; Mediating; Modification; Molecular; Pathway interactions; Petromyzon marinus; Philosophy; Physiology; Regulator Genes; Regulatory Element; Reproducibility; Research; Somatic Cell; Structure; Vertebrates; Work; comparative; functional outcomes; gene function; germline stem cells; histone methylation; migration; next generation; novel; novel strategies; pluripotency; tumorigenesis; vertebrate genome

An individual's genome provides a complete set of instructions for achieving development, regulating physiology and passing heritable information to the next generation. These instructions are encoded in the linear sequence of DNA molecules (e.g. genes) and in the higher-order structures of chromosomes and subchromosomal regions (e.g. regulatory elements). Alterations at any scale can severely impact an individual's health, survival and ability to reproduce. It is therefore not surprising that life has evolved a variety of genes and molecular pathways that contribute to maintaining the integrity of information encoded in the genome, nor is it surprising that independent evolutionary lineages have evolved novel pathways or novel modifications to their ancestral genome biology. Studying these diverse mechanisms can provide critical comparative perspective on the cellular, molecular and evolutionary underpinnings of human genome biology and have the potential to reveal new approaches to modulating related pathways in human. Following this philosophy, my lab has sought to understand the functional and evolutionary mechanisms that underlie the remarkable diversity of genome biologies that exist among deep vertebrate lineages. Our recent work has focused on dissecting the causes and consequences of programmed genome rearrangement (PGR) in the sea lamprey (Petromyzon marinus). In lampreys, PGR involves changes in the physical structure (and content) of the genome that occur in a highly predictable and programmatic manner during early development. These changes result in the reproducible loss of a specific subset of genes from all somatic cell lineages. In total, approximately 20% of the lamprey's genome is eliminated from somatic cells and retained only by germ cells. Recent progress in this line of research has shed light on the cellular/developmental mechanisms of PGR and the functions of eliminated genes. Our analyses of PGR have demonstrated that canonical silencing mechanisms (DNA and histone methylation) contribute to elimination of DNA during PGR, particularly during later stages of elimination. These studies have also revealed that eliminated genes contribute to the development/maintenance of germline when normally expressed and oncogenesis when somatically misexpressed (in other vertebrates). This proposal seeks to continue our efforts in characterizing the mechanisms and functional outcomes of PGR and extend these toward identifying genes and molecular pathways that can impact the biology of the human genome, germ/stem cells and cancer. Proposed studies aim to address several outstanding challenges with respect to PGR: 1) Precisely defining the sequence context of PGR-associated epigenetic changes and their interactions with other molecules, 2) Identifying other pathways that contribute to PGR, especially the earliest stages that involve the targeting of sequences for elimination and the differential migration of eliminated chromatin during anaphase, and 3) Characterizing the function of eliminated genes, particularly in the contexts of genome stability/instability and reprogramming. ! 1!

个体的基因组提供了一整套实现发育、调节 生理学和将可遗传的信息传递给下一代。这些指令编码在 DNA分子(如基因)的线性序列，以及在染色体和 亚染色体区域(例如，调节元件)。任何规模的更改都会严重影响 个体的健康、生存和繁殖能力。因此，生命进化出多样性也就不足为奇了。 这些基因和分子途径有助于维护编码在 基因组，独立的进化谱系进化出新的途径或新的东西也不令人惊讶 对它们祖先基因组生物学的修改。研究这些不同的机制可以提供关键的 人类基因组生物学的细胞、分子和进化基础的比较视角 并有可能揭示调节人类相关通路的新方法。 遵循这一理念，我的实验室试图了解其功能和进化机制 这是存在于深层脊椎动物谱系中的基因组生物学显著多样性的基础。我们的 最近的工作集中在剖析程序性基因组重排的原因和后果 (PGR)在海鳗(Petromyzon Marinus)中。在七鳃鳗中，PGR涉及到物理结构的变化 (和内容)以高度可预测和程序化的方式出现在早期 发展。这些变化导致所有体细胞的特定基因子集的可重复性丢失 血统。总共，大约20%的七鳃鳗基因组从体细胞中被消除并保留下来 只有生殖细胞才能做到。这一系列研究的最新进展揭示了细胞/发育 PGR的发生机制和缺失基因的功能。我们对PGR的分析表明， 规范的沉默机制(DNA和组蛋白甲基化)有助于在PGR过程中消除DNA， 特别是在淘汰的后期阶段。这些研究还揭示了消除的基因 在正常表达和肿瘤发生时有助于生殖系的发展/维持 躯体错误表达(在其他脊椎动物中)。这项提议寻求继续努力，使我们能够 PGR的机制和功能结果，并将其扩展到识别基因和分子 可影响人类基因组、生殖细胞/干细胞和癌症生物学的途径。建议的研究 目的解决与PGR有关的几个突出挑战：1)准确定义序列上下文 与PGR相关的表观遗传学变化及其与其他分子的相互作用，2)识别其他 参与PGR的途径，尤其是涉及靶向序列的最早阶段 后期消除和消除的染色质的差异迁移，以及3)表征 消除基因的功能，特别是在基因组稳定/不稳定和重新编程的背景下。 ！1！