BRD4-mediated regulation of human brain development and function

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My long-term research vision aims to study molecular regulations of brain development and functions. My research program applies two unique technologies: stem cell engineering and computational analysis that are promising approaches to generate various types of cells and tissues from individuals and handle large-scale biological data from the stem cell-derived cell types and tissues.  Brain is one of the most complex and important organs to control our emotional and behavioral processes. Brain is made up of multiple cell types, such as neurons, astrocytes, and microglia, that have their own unique properties and interact each other. Differentiation into each cell type is determined by the unique gene expression program. Histones are basic proteins that condense DNA into a compact form, called chromatin. Importantly, chemical modifications of histone proteins are known to contribute to the cell type-specific gene expression program by perturbing chromatin structure. Although more than 150 histone modifying enzymes have been reported so far, the most of their functional roles in brain development are largely unknown.  BRD4 is one of the modifying enzymes that are heavily expressed in brain and promote acetylation of lysine residues in histone proteins. We previously found that abnormal genomic binding of BRD4 impairs neuronal growth and electrical activation. It has been also reported that BRD4 also regulates glial cell differentiation and immune response of microglia. Although these data implicate that BRD4 is essential for development and function of both neuronal and glial cells in brain, it still remains unclear how BRD4 regulates cellular identity and distinct properties across multiple cell types.  We will differentiate human embryonic stem cells into neurons, astrocytes, and microglia with well-established protocols and investigate 1) genome-wide occupancy and 2) protein-protein interactions of BRD4 across different cell types using cutting-edge genomics and proteomics technologies. Furthermore, given the involvement of BRD4 in cell fate determination in brain, it is questionable 3) whether BRD4 also contributes structural organization of cell types in brain. To address this question, we will grow miniature brains from human embryonic stem cells with three-dimensional culture system and analyze whether BRD4 affects the organization of brain structure by high-resolution imaging analysis. Overall, the research program will employ in vitro tissue modeling and in silico analysis of large-scale datasets to shed light on fundamental epigenetic regulation of human brain development. Throughout the proposed project, students will obtain broad knowledge and expertise in stem cell biology, neuroscience, and bioinformatics.