Epigenomic Regulation in Microglia

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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.