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Functional characterization of DNA methylation in the oligodendrocyte lineage [RNASeq_development]

ABSTRACT: Myelination in the CNS is modulated by interplay between transcription factors and recruitment of chromatin modifying enzymes. Using a network built from genome-wide DNA methylation and transcriptomic profiling of sorted oligodendrocyte lineage cells that integrates oligodendrocyte-specific ChIP-Seq data, we defined a crucial role of DNA methylation in coordinating the transition between progenitor cell cycle arrest and oligodendrocyte differentiation. We further identified DNA methyltransferase 1 (DNMT1) as key regulator of oligodendrocyte survival at this transition point, as we detected severe and extensive developmental hypomyelination only in Olig1cre/+;Dnmt1flox/flox but not in Olig1cre/+;Dnmt3aflox/flox mice or in Cnpcre/+;Dnmt1flox/flox. This phenotype was characterized by decreased expression of genes regulating myelination and lipid metabolism – despite the hypomethylation observed at these genetic loci – and upregulation of cell cycle and DNA-damage pathways. Therefore DNMT1 is a nodal point regulating proliferation, survival, and differentiation in the oligodendrocyte lineage, and is critical for cell number regulation in the developing brain.

ORGANISM(S): Mus musculus

PROVIDER: GSE66029 | GEO | 2016/04/14

SECONDARY ACCESSION(S): PRJNA275720

REPOSITORIES: GEO

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Functional characterization of DNA methylation in the oligodendrocyte lineage [ERRBS]

Project description:Myelination in the CNS is modulated by interplay between transcription factors and recruitment of chromatin modifying enzymes. Using a network built from genome-wide DNA methylation and transcriptomic profiling of sorted oligodendrocyte lineage cells that integrates oligodendrocyte-specific ChIP-Seq data, we defined a crucial role of DNA methylation in coordinating the transition between progenitor cell cycle arrest and oligodendrocyte differentiation. We further identified DNA methyltransferase 1 (DNMT1) as key regulator of oligodendrocyte survival at this transition point, as we detected severe and extensive developmental hypomyelination only in Olig1cre/+;Dnmt1flox/flox but not in Olig1cre/+;Dnmt3aflox/flox mice or in Cnpcre/+;Dnmt1flox/flox. This phenotype was characterized by decreased expression of genes regulating myelination and lipid metabolism â despite the hypomethylation observed at these genetic loci Â â and upregulation of cell cycle and DNA-damage pathways. Therefore DNMT1 is a nodal point regulating proliferation, survival, and differentiation in the oligodendrocyte lineage, and is critical for cell number regulation in the developing brain. Genome wide DNA methylation profiles of FAC-sorted P2 Pdgfra::GFP and P18 Plp1-GFP purified cell samples from mouse brains were generated by ERRBS analysis, in duplicate, using Illumina HiSeq 2000.

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