Determinants of epigenetic inheritance in human stem cell fate decisions

人类干细胞命运决定中表观遗传的决定因素

• 批准号: 10711483
• 负责人: Thelma Escobar
• 金额: $ 41.9万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-20 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711483
• 关键词: Adult Acute Myeloblastic Leukemia; Age; Cell Cycle; Cell division; Cells; Chromatin; Complex; DNA Sequence Alteration; DNA biosynthesis; DNA replication fork; Epigenetic Process; Gene Expression; Genome engineering; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Heritability; Histones; Human; Human Development; Imaging technology; Immune system; In Vitro; Inherited; Molecular; Molecular Chaperones; Mus; NPM1 gene; Nucleosomes; Play; Polycomb; Postdoctoral Fellow; Process; Proteomics; Recycling; Repression; Role; S phase; Shapes; System; embryonic stem cell; epigenome; hematopoietic stem cell self-renewal; human stem cells; induced pluripotent stem cell; nucleophosmin; segregation; self-renewal; stem cell fate

Project summary In hematopoietic stem cells (HSCs), the epigenome confers self-renewal and differentiation functions wherein inheritance of HSC chromatin states is persistent across cell cycles. My postdoctoral studies focused on a fundamental epigenetic feature involving the local recycling of pre-existing, parental nucleosomes, which showed that repressed, but not active, chromatin domains are inherited across DNA replication. While identifying the histone chaperone(s) that facilitate the inheritance of repressed chromatin domains in mouse embryonic stem cells, I discovered that nucleophosmin, NPM1, plays an essential role in this process. NPM1 is a histone chaperone whose genetic mutation and rearrangement are found in ~30% of all adult AML, however its function in normal hematopoiesis remains unknown. Furthermore, key questions persist on the inheritance of H3K27me chromatin domains, such as what brings NPM1 and the polycomb repressive complex 2 (PRC2) to the DNA replication fork during S-phase, how are polycomb chromatin domains inherited in the developing immune system, and whether parental nucleosome segregation has a role in the precise balancing between self-renewal and differentiation capacities that shape a hematopoietic cascade. In this proposal, my group will identify the molecular basis for constructing the heritable human epigenome of HSCs and discover the chromatin dynamics that provide HSCs the ability to both self-renew and differentiate. We will use in vitro human induced pluripotent stem cells and differentiate them to derive a hematopoietic progenitor cell fate. Using this system, we will conduct cutting age genome engineering, proteomics, and imaging technologies to discover the function of histone chaperones and polycomb in constructing the heritable epigenome of HSCs.

项目摘要 在造血干细胞（HSC）中，表观基因组赋予自我更新和分化功能 其中HSC染色质状态的遗传在细胞周期之间持续存在。我的博士后研究集中 关于涉及局部存在的父母核小体的局部回收的基本表观遗传特征 表明在DNA复制中遗传了抑制但不活跃的染色质结构域。尽管 识别促进小鼠中抑制染色质结构域的遗传的组蛋白伴侣 胚胎干细胞，我发现核素NPM1在此过程中起着至关重要的作用。 NPM1是 一个组蛋白伴侣，其基因突变和重排的所有成年AML约有30％，但是 它在正常造血中的功能仍然未知。此外，关键问题仍然存在于继承权上 H3K27ME染色质结构域，例如带来NPM1和Polycomb抑制复合物2（PRC2） 在S期间，DNA复制叉，如何在发育中遗传的多肉状蛋白结构域 免疫系统，以及父母核小体分离是否在确切平衡中起作用 塑造造血级联的自我更新和分化能力。在这个建议中，我的小组将 确定构建HSC的可遗传人类表观基因组的分子基础并发现 染色质动力学提供了HSC的自我更新和分化的能力。我们将在体外使用 人诱导多能干细胞并区分它们以衍生造血祖细胞命运。 使用该系统，我们将进行切割年龄基因组工程，蛋白质组学和成像技术 发现组蛋白伴侣和多康布在构建HSC的遗传表观基因组中的功能。