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Phosphorylation state of ZFP24 controls oligodendrocyte differentiation

ABSTRACT: The zinc finger protein ZFP24 is critical for CNS myelination. Nonetheless, the mechanism by which ZFP24 controls myelination is unknown. Here we use chromatin IP (ChIP) to map ZFP24 binding sites in oligodendrocyte progenitor cells (OPC) and differentiated oligodendrocytes (OLG). We find that ZFP24 directly binds the enhancer regions of genes important for oligodendrocyte differentiation and myelination and mediates their expression. We demonstrate that ZFP24 undergoes phosphorylation and dephosphorylation in oligodendrocyte lineage cells and that ZFP24 binding to DNA is controlled by its phosphorylated state such that only the non-phosphorylated form of the protein, predominantly found in mature oligodendrocytes, mediates expression of myelin protein genes. We have also identified key ZFP24 downstream target genes. Among these, we show that enforced expression of the crucial myelin transcription factor MYRF can rescue myelin proteins gene expression in ZFP24 -ablated cells. Our data also suggest that ZFP24 display overlapping genomic binding sites with the transcription factors MYRF, SOX10, and OLIG2 which are known to control terminal differentiation of oligodendrocytes. Though the human genome contains roughly 700 C2H2-containing zinc finger proteins, the DNA-binding sequences and the biological functions of the vast majority of them are unknown. Our findings provide a direct molecular mechanism by which dephosphorylation of ZFP24 mediates its binding to enhancer regions of genes important for oligodendrocyte differentiation and myelination, controls their expression, and as a result, regulates oligodendrocyte differentiation and CNS myelination.

ORGANISM(S): Mus musculus

PROVIDER: GSE101535 | GEO | 2018/04/10

REPOSITORIES: GEO

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