Functional characterization of DNA methylation in the oligodendrocyte lineage
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Sarah Moyon
PROVIDER: E-GEOD-66047 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
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 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. mRNA profiles of FAC-sorted P2 Pdgfra::GFP and P18 Plp1-GFP purified cell samples from mouse brains were generated by RNA-sequencing, in triplicate, using Illumina HiSeq 2000.
2016-04-14 | E-GEOD-66029 | biostudies-arrayexpress
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 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.
2016-04-14 | E-GEOD-66028 | biostudies-arrayexpress
Project description:Oligodendrocytes derive from progenitors (OPC) through the interplay of epigenetic and transcriptional events. By integrating high-resolution methylomics, RNA-sequencing and multiple transgenic lines, this study defines the role of DNMT1 in developmental myelination. We detected hypermethylation of genes related to cell cycle and neurogenesis during differentiation of OPC, and yet, genetic ablation of Dnmt1 resulted in inefficient OPC expansion and severe hypomyelination associated with ataxia and tremors in mice. This phenotype was not caused by lineage switch or massive apoptosis, but was characterized by a profound defect of differentiation, associated with massive changes in exon-skipping and intron-retention splicing events, and by the activation of an endoplasmic reticulum stress response. Therefore, loss of Dnmt1 in OPC is not sufficient to induce a lineage switch, but acts as an important determinant of the coordination between RNA splicing and protein synthesis, necessary for myelin formation. mRNA profiles of P5 mouse Olig1+/+;Dnmt1flox/flox;Pdgfra-GFP and Olig1cre/+;Dnmt1flox/flox;Pdgfra-GFP sorted OPC were generated by RNA-sequencing, in triplicate, using Illumina HiSeq 2500.
2016-04-14 | E-GEOD-79018 | biostudies-arrayexpress
Project description:Myelination by oligodendrocytes in the central nervous system (CNS) is essential for proper brain function, yet the molecular determinants that control this process remain poorly understood. The basic helix-loop-helix transcription factors Olig1 and Olig2 promote myelination, whereas bone morphogenetic protein (BMP) and Wnt/?-catenin signaling inhibit myelination. Here we show that these opposing regulators of myelination are functionally linked by the Olig1/2 common target Smad-interacting protein-1 (Sip1). We demonstrate that Sip1 is an essential modulator of CNS myelination. Sip1 represses differentiation inhibitory signals by antagonizing BMP receptor-activated Smad activity while activating crucial oligodendrocyte-promoting factors. Importantly, a key Sip1-activated target, Smad7, is required for oligodendrocyte differentiation and partially rescues differentiation defects caused by Sip1 loss. Smad7 promotes myelination by blocking the BMP- and ?-catenin-negative regulatory pathways. Thus, our findings reveal that Sip1-mediated antagonism of inhibitory signaling is critical for promoting CNS myelination and point to new mediators for myelin repair. ChIP-seq was performed to identify Olig2 direct target genes in oligodendrocytes during oligodendrocyte differentiation.
2012-08-31 | E-GEOD-40506 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE40506: Genome-wide mapping of Olig2 targets in primary oligodendrocytes GSE40510: Expression data from Sip1 cKO and control mice spinal cord Refer to individual Series
2012-08-31 | E-GEOD-40431 | biostudies-arrayexpress
Project description:The generation of myelinating cells in the central nervous system (CNS) requires the initiation of specific gene-expression programs in oligodendrocytes. We reasoned that miRNAs could play an important role in this process by regulating critical developmental genes. Microarray profiling of cultured oligodendrocytes identifies the miR-17~92 family of miRNA cluster as highly enriched miRNAs in oligodendrocytes.We specifically deleted the miR-17~92 cluster in oligodendrocytes using the 2´3´-cyclic nucleotide 3´-phosphodiesterase (CNP)-Cre mice. Absence of miR-17~92 leads to a reduction of oligodendrocyte number in vivo and we find that the expression of these miRNAs in primary cultures of oligodendrocytes promotes cell proliferation by influencing Akt signalling. Together, these results suggest that the miRNA pathway is essential in determining oligodendroglial cell number and that the miR-17~92 cluster is crucial in this process. miRNA microarray profiling was used for the identification of miRNAs enriched in oligodendrocytes. Total RNA lysates from primary oligodendroctes compared to primary astrocytes were analysed regarding their miRNA levels. Three independent samples for each of the two cell types were used. The study was initially designed with a comparison of oligodendrocytes, astrocytes and microglia. However, only the comparison of oligodendrocytes and astrocytes is discussed in the present study.
2010-06-08 | E-GEOD-21799 | biostudies-arrayexpress
Project description:The generation of myelinating cells in the central nervous system (CNS) requires the initiation of specific gene-expression programs in oligodendrocytes. We reasoned that miRNAs could play an important role in this process by regulating critical developmental genes. Microarray profiling of cultured oligodendrocytes identifies the miR-17~92 family of miRNA cluster as highly enriched miRNAs in oligodendrocytes.We specifically deleted the miR-17~92 cluster in oligodendrocytes using the 2´3´-cyclic nucleotide 3´-phosphodiesterase (CNP)-Cre mice. Absence of miR-17~92 leads to a reduction of oligodendrocyte number in vivo and we find that the expression of these miRNAs in primary cultures of oligodendrocytes promotes cell proliferation by influencing Akt signalling. Together, these results suggest that the miRNA pathway is essential in determining oligodendroglial cell number and that the miR-17~92 cluster is crucial in this process. Transcriptome microarray profiling was used for the identification of mRNAs enriched in oligodendrocytes. Total RNA lysates from primary oligodendroctes compared to primary astrocytes were analysed regarding their mRNA levels. Three independent samples for each of the two cell types were used. The study was initially designed with a comparison of oligodendrocytes, astrocytes and microglia. However, only the comparison of oligodendrocytes and astrocytes is discussed in the present study.
2010-06-08 | E-GEOD-21797 | biostudies-arrayexpress
Project description:In multiple sclerosis (MS) and experimental models of demyelination, myelin repair is mostly achieved by oligodendrocyte precursor cells (OPCs). To gain insight into the biological specificity of these adult precursors, in the perspective to better understand why remyelination often fails in MS, we performed a micro-array analysis on purified populations of murine OPCs and oligodendrocytes. We demonstrated that, in a control environment, M-bM-^@M-^\quiescentM-bM-^@M-^] adult OPCs are more mature than neonatal OPCs, with a mRNA profile closer to oligodendrocytes. However, when demyelination occurs, adult OPCs revert to an immature gene expression profile, acquiring higher migration and faster differentiation capacities. Among the many genes differentially regulated by these M-bM-^@M-^\activatedM-bM-^@M-^] adult OPCs, genes of the innate immune response, IL1M-NM-2 and CCL2 were strongly upregulated after demyelination, with increased protein expression in experimental demyelinating lesions and within MS plaques. We first showed in vitro that both IL1M-NM-2 and CCL2 M-bM-^@M-^\accountM-bM-^@M-^] for increased migration capacities of adult OPCs, an effect that is suppressed by corresponding receptor blockade. Focusing on Ccl2, we then demonstrated that lentiviral over-expression of Ccl2 increases motility of M-bM-^@M-^\quiescentM-bM-^@M-^] adult OPCs, which become as mobile as M-bM-^@M-^\activatedM-bM-^@M-^] adult OPCs. This in vitro gain of function was further confirmed in vivo, by showing an increased migration of grafted CG4 oligodendroglial cells over-expressing-Ccl2. These results, demonstrating that M-bM-^@M-^\activatedM-bM-^@M-^] adult OPCs upregulate immune cues favouring their migration, open new perspective of demyelination-induced immune-glial interactions, which might influence both oligodendroglial and inflammatory cells, therefore play a key role in lesion fate in multiple sclerosis. In this study, we loaded purified population of progenitors of oligodendrocytes (OPCs) (from neonatal, 2-month-old, 2-month-old and cuprizone-treated brains) and of mature oligodendrocytes (OLs) (2-month-old brains) and compared their gene expression. We compared gene expression of neonatal OPCs, adult OPCs, adult OLs and adult OPCs from control conditions and from demyelinating conditions, using 3 to 4 independant replicates in each group.
2014-11-06 | E-GEOD-48872 | biostudies-arrayexpress
Project description:We examine the role of Klf6 in oligodendrocyte progenitor cells and determine that Klf6 acts in part through direct regulation of gp130 signaling and nuclear import via importin-α5 (Impα5), a key controller of nuclear trafficking. Examination of Klf6 DNA binding in two different stages of differentiation
2016-04-01 | E-GEOD-79243 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-04-01 | E-GEOD-79245 | biostudies-arrayexpress