Epigenomic Regulation in Microglia

最新进展：发育中的神经系统和免疫系统之间的相互作用对大脑的正常发育至关重要。小胶质细胞是大脑的免疫细胞，在大脑发育过程中直接与神经元相互作用，以控制神经元的数量和连接。小胶质细胞也是一种独特的脑细胞类型，因为这些细胞出生于肝脏，然后迁移到大脑，在那里它们与发育中的神经元一起成熟。小胶质细胞如何调节基因对这一成熟过程的重要性还没有很好的理解。表观遗传机制允许在不断变化的环境中调节基因表达，对于从植物到动物的各种系统中的细胞成熟和功能至关重要。** 目标：我的长期目标是更深入地了解表观遗传调节因子如何指导小胶质细胞成熟的基本规则。我的短期目标是检验DNA甲基化和组蛋白乙酰化这两种表观遗传调节形式协调小胶质细胞成熟和稳态的假设。** 方法：第一个目标是研究小胶质细胞发育过程中DNA甲基化和组蛋白乙酰化之间的时间关系。通过绘制多个时间点，我们将揭示与基因表达调控相关的表观遗传标记的时间进展。这些全面的表观基因组图谱将在我们的实验室网站上形成一个新的、公开的研究资源。第二个目标将测试组蛋白去乙酰化酶Hdac3在调节小胶质细胞成熟中的作用。Hdac3在小胶质细胞发育过程中高度表达，但其在小胶质细胞成熟中的功能尚不清楚。我们将通过在小胶质细胞成熟过程中删除这种酶来测试Hdac3的作用，并检查对小胶质细胞形态，基因表达和表观基因组的影响。第三个目标将因果测试组蛋白乙酰化在驱动小胶质细胞基因表达中的作用。通过组蛋白乙酰化酶直接特异性靶向发育关键的小胶质细胞基因，我将测试这些酶直接改变组蛋白乙酰化和基因表达的能力。这将提供第一个证据，表明在小胶质细胞中观察到的动态表观基因组标记导致基因表达的变化。HQP：该研究计划将为两名研究生，三名本科暑期学生和一名研究人员提供培训机会，他们被招募来促进公平的机会，并根据UBC公平和多样性战略计划为代表性不足的群体提供培训。影响：这项工作将为小胶质细胞发育中基因表达的调控提供新的理解。从这一基础生物学研究中获得的知识将在表观遗传学、神经科学和发育生物学领域产生广泛的影响。

Recent Progress: Interactions between the developing nervous and immune systems are critical for normal brain development. Microglia, the brain's immune cells, directly interact with neurons during brain development to control neuronal numbers and connections. Microglia are also a unique brain cell type in that these cells are born in the liver and then migrate to the brain where they mature alongside developing neurons. How microglia regulate genes important for this maturation process is not well understood. Epigenetic mechanisms that allow the regulation of gene expression in a changing environment are critical for cellular maturation and function in a wide variety of systems from plants to animals. ******Objectives: My long-term objective is to gain a deeper knowledge of the fundamental rules governing how epigenetic regulators direct microglial maturation. My short-term objective is to test the hypothesis that DNA methylation and histone acetylation, two forms of epigenetic regulation, coordinate microglial maturation and homeostasis. ******Methods: The first objective will examine the temporal relationship between DNA methylation and histone acetylation during microglial development. By mapping multiple timepoints we will uncover the temporal progression of epigenetic marks that tie to regulation of gene expression. These comprehensive epigenomic maps will form a novel, publicly available research resource on our lab website. The second objective will test the role for the histone deacetylase Hdac3 in regulating microglial maturation. Hdac3 is highly expressed in microglia across development, but its function in microglial maturation is unknown. We will test the role of Hdac3 by deleting this enzyme specifically in microglia during microglial maturation and examine the resulting impact on microglial morphology, gene expression, and the epigenome. The third objective will causally test the role of histone acetylation in driving microglial gene expression. Through specific targeting of histone acetylation enzymes directly to developmentally critical microglial genes, I will test the ability of these enzymes to directly alter histone acetylation and gene expression. This will provide the first evidence that dynamic epigenomic marks observed in microglia are causing changes in gene expression.******HQP: This research program will provide training opportunities for two graduate students, three undergraduate summer students, and one research staff, recruited to promote equitable opportunity and training for underrepresented groups as per the UBC Equity and Diversity Strategic plan.******Impact: Together this work will provide new understanding of how gene expression is regulated in microglial development. Knowledge gained from this basic biological research will have widespread implications in the fields of epigenetics, neuroscience, and developmental biology.