Molecular determinants of oligodendrocyte differentiation and myelination

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Oligodendrocytes are the myelinating glia of the central nervous system. These cells extend numerous processes that wrap the neuronal axons in a compact membranous sheath. The myelin sheath allows for fast, efficient neurotransmission, which is important for both coordinated movement and higher cognitive functions. Early postnatal development is the most intense period of myelination in the brain. During this time, stem cells undergo changes through several distinct stages, migrating throughout the cortex and underlying white matter to reach a mature, myelinating phenotype. Progress through these stages is governed by transcriptional networks regulating gene expression. While our knowledge of individual transcription factors that are involved in oligodendrogenesis continues to expand, ultimately these need to be considered in the context of a broader regulatory network. Several epigenetic modifiers, including histone acetyltransferases (HATs) and histone deacetylases (HDACs), modulate the accessibility of chromatin to regulate transcription. My long-term vision for a NSERC-funded research program is to define the molecular players and interaction networks that regulate developmental myelination. In this initial research proposal, my team will work to systematically define the role of HATs and HDACs in the proliferation and differentiation of oligodendrocyte progenitor cells. We will characterize the expression levels and subcellular location of acetyltransferases and deacetylases during each stage of differentiation to determine key regulators of oligodendrogenesis. Integrated genomic and proteomic approaches will be employed to identify transcriptional complexes regulating gene expression providing a rigorous, cutting-edge training environment for undergraduate and graduate students. The emerging role of acetyltransferases and deacetylases, both through modification of histones and other target proteins (including transcription factors), signifies the importance of these post-translational modifications in regulating cellular function. Relatively little is known regarding the specific roles of many of these enzymes in cell differentiation, such as how they are targeted to different regions of the genome and the extent of overlap of function between the different classes. Thus, my research program will contribute to the fundamental understanding of how the coordinated actions of transcription factors and epigenetic modifiers lead to the highly orchestrated and tightly regulated gene expression in the developing brain.