Myelin in the central nervous system is the specialized extension of the oligodendrocyte cell membrane, which wraps axons to allow for salutatory conduction and to provide necessary trophic support. A number of pathological conditions, including genetic mutations, maternal nutritional deficiencies, and hypoxia at birth, can contribute to improper myelin formation in infancy. Moreover, myelin remains vulnerable in adulthood to environmental insults such as alcohol intoxication, viral infection, and autoimmunity. Decreases in white matter density have been associated with psychiatric disorders, including major depressive disorder, schizophrenia, and autism, while loss of myelin due to autoimmune attack, as seen with multiple sclerosis, can result in devastating paralysis. Therefore, it is of great relevance to a wide array of neurological and psychiatric disorders to better understand the processes regulating oligodendrocyte development and myelin formation. This research proposal tests the hypothesis that DNA methylation is an essential epigenetic mechanism required for the acquisition of an oligodendrocyte identity by cooperating with histone deacetylation.
In Aim 1, I will identify the presence of a protein complex between the enzymes responsible for DNA methylation and histone deacetylation, as well as asses the co-regulatory role this complex plays in regulating gene expression.
In Aim 2, I will use conditional ablation of the DNA methyltransferases in the oligodendrocyte lineage to validate their role in developmental myelination. Finally, in Aim 3, I will extend these studies into a disease model of demyelination to ascertain if developmental mechanisms are recapitulated during remyelination. Overall, the results of this proposal will advance our knowledge in the field of oligodendrogenesis and have important consequences toward furthering our understanding of myelin repair.
Oligodendrocytes form sheaths around axons known as myelin that facilitates conduction of signals from the brain, and the loss of myelin has been associated with psychiatric disorders, such as major depressive disorder and schizophrenia, and can result in devastating paralysis, as seen in multiple sclerosis. This study seeks to understand the role of DNA methylation in oligodendrocyte development and myelin formation, so that we may better understand these disease processes and the variability in recovery.
|Huynh, Jimmy L; Garg, Paras; Thin, Tin Htwe et al. (2014) Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains. Nat Neurosci 17:121-30|
|Narayanan, Manikandan; Huynh, Jimmy L; Wang, Kai et al. (2014) Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases. Mol Syst Biol 10:743|
|Huynh, Jimmy L; Casaccia, Patrizia (2013) Epigenetic mechanisms in multiple sclerosis: implications for pathogenesis and treatment. Lancet Neurol 12:195-206|