Functional Analysis of Programmed Genome Rearrangement

程序化基因组重排的功能分析

• 批准号: 10330955
• 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/10330955
• 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!

一个人的基因组提供了一套完整的指令，用于实现发展，调节 生理学和传递遗传信息给下一代。这些指令被编码在 DNA分子（如基因）的线性序列和染色体的高级结构， 亚染色体区域（例如调节元件）。任何规模的改变都可能严重影响 个体的健康、生存和繁殖能力。因此，生命进化出各种各样的 基因和分子通路，有助于保持编码在细胞中的信息的完整性， 基因组，也不奇怪，独立的进化谱系已经进化出新的途径或新的 对他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观点 并有可能揭示调节人类相关通路的新方法。 根据这一理念，我的实验室试图了解功能和进化机制， 这是存在于深层脊椎动物谱系中的基因组生物学的显著多样性的基础。我们 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)海七鳃鳗（Petromyzon marinus）。在七鳃鳗中，PGR涉及物理结构的变化， (and在早期阶段，基因组以高度可预测和程序化的方式发生， 发展这些变化导致所有体细胞中特定基因亚群的可重复丢失 血统总的来说，大约20%的七鳃鳗的基因组从体细胞中消除并保留下来， 只有生殖细胞。这一研究领域的最新进展揭示了细胞/发育 PGR的作用机制和被消除基因的功能。我们对PGR的分析表明， 典型的沉默机制（DNA和组蛋白甲基化）有助于PCR期间DNA的消除， 特别是在淘汰的后期阶段。这些研究还表明， 当正常表达时有助于生殖系的发育/维持，当 体细胞错误表达（在其他脊椎动物中）。这项建议旨在继续努力， PGR的机制和功能结果，并将其扩展到识别基因和分子 可能影响人类基因组、生殖/干细胞和癌症生物学的途径。拟定研究 旨在解决PCR方面的几个突出挑战：1）精确定义序列背景 PGR相关的表观遗传变化及其与其他分子的相互作用，2）识别其他 这些通路有助于PGR，特别是涉及靶向PGR的序列的最早阶段。 消除和消除的染色质在后期的差异迁移，和3）表征 消除基因的功能，特别是在基因组稳定性/不稳定性和重编程的背景下。 !一个！