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  • Quinupristin-Dalfopristin Complex mesylate Myelination by ol

    2021-09-06

    Myelination by oligodendrocytes is required for saltatory nerve impulse conduction and proper CNS function (Bercury and Macklin, 2015). Defects in myelination and remyelination impair saltatory nerve conduction and functional connectivity leading to cognitive, behavioral, and motor deficits in neurological disorders, including multiple sclerosis and leukodystrophies (Franklin and Goldman, 2015, McKenzie et al., 2014, Trapp et al., 1998). Oligodendrocyte precursor Quinupristin-Dalfopristin Complex mesylate (OPCs), which develop from neural progenitors in the CNS, proliferate and differentiate to form mature oligodendrocytes through a stepwise process (Kessaris et al., 2006, Rowitch, 2004, Wegner and Stolt, 2005). Chromatin modification and remodeling is critical for the oligodendrocyte differentiation process, and their dysregulation has been implicated in neurological diseases (Emery and Lu, 2015, Hota and Bruneau, 2016, Kuspert and Wegner, 2016). ATP-dependent chromatin remodeling enzymes use ATP as an energy source to gate the accessibility of chromatin to transcriptional modulators, and regulate various biological processes, including cell growth, differentiation, and regeneration (Hota and Bruneau, 2016, Wu et al., 2009). There are at least four chromatin remodeler families depending on their catalytic ATPase subunit: CHD, INO80, ISWI, and SWI/SNF families (Hota and Bruneau, 2016). The BRG1-containing SWI/SNF-related BAF complex is required for the developmental transition from Olig1+ lineage progenitors or neural progenitors to oligodendrocytes (Bischof et al., 2015, Matsumoto et al., 2016, Yu et al., 2013). In addition, BRG1, together with the lineage transcription factor Olig2, activates a downstream chromatin remodeler CHD7 to control OPC differentiation and the timing of myelination in the CNS (He et al., 2016). At present, whether and how these chromatin remodelers act in concert with temporal or spatial specificity for CNS myelinogenesis and regeneration remains elusive. Additionally, how chromatin remodeling enzymes coordinate with the histone-modifying machinery to regulate the transcriptional program for oligodendrocyte myelination has not been fully defined. Although CHD8 is expressed broadly in the developing brain, including neurons and glial cells, and has been implicated in neuronal development, functions, and animal behaviors by analyzing heterozygous Chd8+/− mutant animals or in utero knockdown experiments (Cotney et al., 2015, Durak et al., 2016, Gompers et al., 2017, Katayama et al., 2016, Platt et al., 2017), the important questions regarding the cell-type-specific function of CHD8 are not resolved by previous studies. Since ASD patients with CHD8 mutations exhibit severe white matter abnormalities, whether the myelination defect of ASD brains is caused by cell-autonomous and cell non-autonomous actions of CHD8 mutations remains unanswered. Defining the lineage-specific molecular and cellular mechanisms of how Chd8 mutations cause white matter abnormalities will provide a better understanding of and treatment strategies for this complex disease. By generating conditional Chd8 knockout mice lacking Chd8 in different neural cell types, we identify a critical, previously unrecognized cell-intrinsic function of CHD8 in oligodendrocyte lineage progression with distinct specificity across CNS regions, as well as in remyelination after demyelinating injury. Chromatin occupancy profiling reveals that CHD8 establishes an accessible chromatin landscape and initiates a successive chromatin remodeling cascade to activate lineage progression. We further show that CHD8 recruits KMT2 histone methyltransferase complexes to promote transcriptional programs necessary for oligodendrocyte differentiation. Elevation of H3K4 trimethylation levels by inhibition of KDM5 histone demethylases partially restores the dysmyelinating phenotype in Chd8-mutant mice. Collectively, our studies provide evidence that a successive cascade of chromatin remodeling events through a CHD8-BRG1-CHD7 axis establishes an accessible chromatin landscape to orchestrate sequential oligodendrocyte lineage progression and enforces developmental checkpoints for establishing oligodendrocyte identity. Our findings point to the potential benefit of modulating CHD8 complex activity to enhance (re)myelination programs in neurological disorders such as ASD or after demyelination.