Myelination in the central nervous system (CNS) by oligodendrocytes (OLs) is required for rapid propagation of action potentials. Myelination defects and demyelinating diseases have been associated with a series of mental health-related disorders, including autism spectrum disorders, Down syndrome, CHARGE syndrome, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, and schizophrenia. At present, however, the mechanistic basis for myelinogenesis and the factors that promote myelin repair have not been fully understood. A large body of work has shown that chromatin-remodeling events govern the transcriptional and epigenetic establishment of cellular differentiation programs. Chromatin remodeling enzymes including histone modifying enzymes and ATP-dependent chromatin remodelers modulate local chromatin structure and facilitate recruitment of essential factors required for gene expression. In previous funding cycle, we demonstrated a critical role of Brg1 (Brahma-related gene-1), the central catalytic subunit of SWI/SNF-like chromatin-modifying enzymatic complexes in the initiation of OPC differentiation. In the previous funding cycle, we demonstrate that Brg1/Smarca4, the central catalytic subunit of SWI/SNF-like chromatin-modifying complexes, is critical for initiation of OPC differentiation, which is prerequisite for subsequent myelination. We further identify a CHARGE syndrome-related Chd7 (chromodomain helicase DNA binding protein 7) as a common target of Brg1/Olig2 during OL development. In this study, we find that an autism spectrum disorder-associated chromatin remodeler Chd8 is highly enriched in myelinating cells in the CNS. Deletion of Chd8 in the oligodendrocyte lineage resulted in severe myelination deficits, suggesting that Chd8 is critical for the control of CNS myelination. The goal of this proposal is to gain a better insight into the molecular basis of the myelination process regulated by Chd8 and its downstream genes. We will utilize conditional in vivo mutagenesis approaches to define the role of Chd8 in CNS myelination and myelin repair by analyzing newly generated conditional knockout mouse strains in a spatiotemporally controlled manner. In addition, we will identify and characterize the direct targets of Chd8 that control the myelination program by employing a combination of genome-wide RNA-sequencing and chromatin-immunoprecipitation-sequencing strategies. The long-term goal of the research proposed here is to foster the development of agents that modulate the activity of Chd8 and its downstream effectors to promote myelination and, of urgent clinical relevance, remyelination. The proposed studies will not only advance our understanding of the mechanisms of CNS myelination, but also identify potential therapeutic targets to promote oligodendrocyte regeneration and myelin repair for the patients with dys- and demyelination-associated disorders including learning disability and mental illnesses.
Myelination defects and demyelinating diseases have been associated with a series of mental health-related disorders, including autism spectrum disorders, Down syndrome, CHARGE syndrome, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, and schizophrenia. The studies proposed in research plans will provide a better understanding of molecular and chromatin remodeling control of CNS myelination and remyelination. They will not only have scientific merits but also could offer new strategies in treating patients with dys- and demyelination-associated disorders including learning disability and mental illnesses.
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