Epigenetic Regulation of Oligodendrocyte Development and Regeneration in the Central Nervous System

Oligodendrocytes (OLs) produce myelin sheaths that electrically insulate axons and promote rapid propagation of action potentials in the CNS. The onset and timing of CNS myelination and remyelination requires precise coordination between epigenetic programming and transcriptional regulation. In this thesis, I present my findings on two epigenetic regulatory complexes Chd7/Sox10 and lncOL1/Suz12 in CNS myelination and remyelination. First, we show that chromatin remodeler Chd7 is required for proper onset of CNS myelination and remyelination. Genome-occupancy analyses, coupled with transcriptome profiling, reveal that Chd7 interacts with Sox10 and targets the enhancers of key myelinogenic genes, and identify novel Chd7 targets including bone formation regulators Osterix/Sp7 and Creb3l2, which are also critical for oligodendrocyte maturation. Thus, Chd7 coordinates with Sox10 to regulate the initiation of myelinogenesis and acts as a molecular nexus of regulatory networks that account for the development of a seemingly diverse array of lineages including oligodendrocytes and osteoblasts, pointing to the hitherto previously uncharacterized Chd7 functions in white matter pathogenesis in CHARGE syndrome. To understand the role of lncRNAs in CNS myelination, we establish dynamic expression profiles of lncRNAs at different stages of oligodendrocyte development and uncover a cohort of stage-specific oligodendrocyte-restricted lncRNAs including a conserved chromatinassociated lncOL1. Genetic inactivation of lncOL1 causes defects in CNS myelination and remyelination following injury. Functional analyses illustrate that lncOL1 interacts with Suz12, a component of PRC2, to promote oligodendrocyte maturation in part through Suz12-mediated repression of a differentiation inhibitory network that maintains the precursor state. Collectively, these studies show that epigenetic circuitry between lncRNAs and transcription factors with chromatin-modifying complexes play roles in balancing inhibitory and activating gene program, allowing the timely CNS myelination and myelin repair.