Transcription factor-dependent differences in cluster composition and transition states of oligodendrocyte differentiation from human stem cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA744097 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15048827.fastq.gz | Fastqsanger.gz | |||
| SRR15048828.fastq.gz | Fastqsanger.gz | |||
| SRR15048829.fastq.gz | Fastqsanger.gz |
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Project description:Oligodendrocytes (OLs) are critical for myelination and are implicated in several brain disorders. Directed differentiation of human induced OLs (iOLs) from pluripotent stem cells can be achieved by forced expression of different combinations of the transcription factors SOX10 (S), OLIG2 (O) and NKX6.2 (N). Here, we applied quantitative image analysis and single-cell transcriptomics to compare different transcription factor combinations for their efficacy towards robust OL lineage conversion. Compared with S alone, the combination of SON significantly increases the number of myelin basic protein-positive iOLs and generates iOLs with a more complex morphology and higher expression levels of myelin-marker genes . The analysis of RNA velocity of individual cells reveals that S generates a population of volatile oligodendrocyte-precursor cells (OPCs) that appear to be more immature than those generated by SON and to display distinct molecular properties. Our analysis suggests that protocols for generating iOPCs or iOLs should be chosen depending on the intended application.
2022-01-31 | GSE179516 | GEO
Project description:Cellular maturation is an adaptive process essential for tissue formation and function, yet distinct from the initial steps of differentiation and cell fate specification. Understanding the regulation of cell maturation may inform underlying mechanisms of disease or new approaches to regenerative medicine. In the central nervous system, failed generation of mature oligodendrocytes contributes to numerous diseases including multiple sclerosis. Here, we report a transcriptional mechanism that governs the timing of oligodendrocyte maturation. After differentiation, the transcription factor SOX6 redistributes from super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggesting that failed maturation contributes to disease pathology. Administration of a Sox6-targeting antisense oligonucleotide in postnatal mice drove precocious oligodendrocyte maturation. Our findings reveal that SOX6 governs oligodendrocyte maturation and that its targeting could inform therapeutic strategies for enhancing myelin regeneration in neurodevelopmental and neurodegenerative diseases.
2023-09-01 | GSE183160 | GEO
Project description:Cellular maturation is an adaptive process essential for tissue formation and function, yet distinct from the initial steps of differentiation and cell fate specification. Understanding the regulation of cell maturation may inform underlying mechanisms of disease or new approaches to regenerative medicine. In the central nervous system, failed generation of mature oligodendrocytes contributes to numerous diseases including multiple sclerosis. Here, we report a transcriptional mechanism that governs the timing of oligodendrocyte maturation. After differentiation, the transcription factor SOX6 redistributes from super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggesting that failed maturation contributes to disease pathology. Administration of a Sox6-targeting antisense oligonucleotide in postnatal mice drove precocious oligodendrocyte maturation. Our findings reveal that SOX6 governs oligodendrocyte maturation and that its targeting could inform therapeutic strategies for enhancing myelin regeneration in neurodevelopmental and neurodegenerative diseases.
2024-11-02 | GSE280851 | GEO
Project description:Cellular maturation is an adaptive process essential for tissue formation and function, yet distinct from the initial steps of differentiation and cell fate specification. Understanding the regulation of cell maturation may inform underlying mechanisms of disease or new approaches to regenerative medicine. In the central nervous system, failed generation of mature oligodendrocytes contributes to numerous diseases including multiple sclerosis. Here, we report a transcriptional mechanism that governs the timing of oligodendrocyte maturation. After differentiation, the transcription factor SOX6 redistributes from super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggesting that failed maturation contributes to disease pathology. Administration of a Sox6-targeting antisense oligonucleotide in postnatal mice drove precocious oligodendrocyte maturation. Our findings reveal that SOX6 governs oligodendrocyte maturation and that its targeting could inform therapeutic strategies for enhancing myelin regeneration in neurodevelopmental and neurodegenerative diseases.
2023-09-01 | GSE182558 | GEO
Project description:Cellular maturation is an adaptive process essential for tissue formation and function, yet distinct from the initial steps of differentiation and cell fate specification. Understanding the regulation of cell maturation may inform underlying mechanisms of disease or new approaches to regenerative medicine. In the central nervous system, failed generation of mature oligodendrocytes contributes to numerous diseases including multiple sclerosis. Here, we report a transcriptional mechanism that governs the timing of oligodendrocyte maturation. After differentiation, the transcription factor SOX6 redistributes from super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggesting that failed maturation contributes to disease pathology. Administration of a Sox6-targeting antisense oligonucleotide in postnatal mice drove precocious oligodendrocyte maturation. Our findings reveal that SOX6 governs oligodendrocyte maturation and that its targeting could inform therapeutic strategies for enhancing myelin regeneration in neurodevelopmental and neurodegenerative diseases.
2023-09-01 | GSE182245 | GEO
Project description:Cellular maturation is an adaptive process essential for tissue formation and function, yet distinct from the initial steps of differentiation and cell fate specification. Understanding the regulation of cell maturation may inform underlying mechanisms of disease or new approaches to regenerative medicine. In the central nervous system, failed generation of mature oligodendrocytes contributes to numerous diseases including multiple sclerosis. Here, we report a transcriptional mechanism that governs the timing of oligodendrocyte maturation. After differentiation, the transcription factor SOX6 redistributes from super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggesting that failed maturation contributes to disease pathology. Administration of a Sox6-targeting antisense oligonucleotide in postnatal mice drove precocious oligodendrocyte maturation. Our findings reveal that SOX6 governs oligodendrocyte maturation and that its targeting could inform therapeutic strategies for enhancing myelin regeneration in neurodevelopmental and neurodegenerative diseases.
2023-09-01 | GSE181952 | GEO
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 (OLs) are critical for myelination and are implicated in several brain disorders. Directed differentiation of human-induced OLs (iOLs) from pluripotent stem cells can be achieved by forced expression of different combinations of the transcription factors SOX10 (S), OLIG2 (O), and NKX6.2 (N). Here, we applied quantitative image analysis and single-cell transcriptomics to compare different transcription factor (TF) combinations for their efficacy towards robust OL lineage conversion. Compared with S alone, the combination of SON increases the number of iOLs and generates iOLs with a more complex morphology and higher expression levels of myelin-marker genes. RNA velocity analysis of individual cells reveals that S generates a population of oligodendrocyte-precursor cells (OPCs) that appear to be more immature than those generated by SON and to display distinct molecular properties. Our work highlights that TFs for generating iOPCs or iOLs should be chosen depending on the intended application or research question, and that SON might be beneficial to study more mature iOLs while S might be better suited to investigate iOPC biology.
| S-EPMC8773672 | biostudies-literature
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 – 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.
2016-04-14 | GSE66029 | GEO