Epigenetic priming of immune/inflammatory pathways activation and abnormal activity of cell cycle pathway in a perinatal model of white matter injury
Abstract Prenatal inflammatory insults accompany prematurity and provoke diffuse white matter injury (DWMI), which is associated with increased risk of neurodevelopmental pathologies, including autism spectrum disorders. DWMI results from maturation arrest of oligodendrocyte precursor cells (OPCs),...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-12-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05483-4 |
| _version_ | 1797980425023389696 |
|---|---|
| author | Anne-Laure Schang Juliette Van Steenwinckel Zoi S. Ioannidou Julia Lipecki Charlotte Rich-Griffin Kate Woolley-Allen Nigel Dyer Tifenn Le Charpentier Patrick Schäfer Bobbi Fleiss Sascha Ott Délara Sabéran-Djoneidi Valérie Mezger Pierre Gressens |
| author_facet | Anne-Laure Schang Juliette Van Steenwinckel Zoi S. Ioannidou Julia Lipecki Charlotte Rich-Griffin Kate Woolley-Allen Nigel Dyer Tifenn Le Charpentier Patrick Schäfer Bobbi Fleiss Sascha Ott Délara Sabéran-Djoneidi Valérie Mezger Pierre Gressens |
| author_sort | Anne-Laure Schang |
| collection | DOAJ |
| description | Abstract Prenatal inflammatory insults accompany prematurity and provoke diffuse white matter injury (DWMI), which is associated with increased risk of neurodevelopmental pathologies, including autism spectrum disorders. DWMI results from maturation arrest of oligodendrocyte precursor cells (OPCs), a process that is poorly understood. Here, by using a validated mouse model of OPC maturation blockade, we provide the genome-wide ID card of the effects of neuroinflammation on OPCs that reveals the architecture of global cell fate issues underlining their maturation blockade. First, we find that, in OPCs, neuroinflammation takes advantage of a primed epigenomic landscape and induces abnormal overexpression of genes of the immune/inflammatory pathways: these genes strikingly exhibit accessible chromatin conformation in uninflamed OPCs, which correlates with their developmental, stage-dependent expression, along their normal maturation trajectory, as well as their abnormal upregulation upon neuroinflammation. Consistently, we observe the positioning on DNA of key transcription factors of the immune/inflammatory pathways (IRFs, NFkB), in both unstressed and inflamed OPCs. Second, we show that, in addition to the general perturbation of the myelination program, neuroinflammation counteracts the physiological downregulation of the cell cycle pathway in maturing OPCs. Neuroinflammation therefore perturbs cell identity in maturing OPCs, in a global manner. Moreover, based on our unraveling of the activity of genes of the immune/inflammatory pathways in prenatal uninflamed OPCs, the mere suppression of these proinflammatory mediators, as currently proposed in the field, may not be considered as a valid neurotherapeutic strategy. |
| first_indexed | 2024-04-11T05:54:15Z |
| format | Article |
| id | doaj.art-5d91fa03d0d040c8a238ea7913f823ed |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-11T05:54:15Z |
| publishDate | 2022-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-5d91fa03d0d040c8a238ea7913f823ed2022-12-22T04:41:56ZengNature Publishing GroupCell Death and Disease2041-48892022-12-01131211910.1038/s41419-022-05483-4Epigenetic priming of immune/inflammatory pathways activation and abnormal activity of cell cycle pathway in a perinatal model of white matter injuryAnne-Laure Schang0Juliette Van Steenwinckel1Zoi S. Ioannidou2Julia Lipecki3Charlotte Rich-Griffin4Kate Woolley-Allen5Nigel Dyer6Tifenn Le Charpentier7Patrick Schäfer8Bobbi Fleiss9Sascha Ott10Délara Sabéran-Djoneidi11Valérie Mezger12Pierre Gressens13Université Paris Cité, Epigenetics and Cell Fate, CNRSUniversité Paris Cité, NeuroDiderot, InsermSchool of Life Sciences, University of WarwickSchool of Life Sciences, University of WarwickSchool of Life Sciences, University of WarwickSchool of Life Sciences, University of WarwickBioinformatics Research Technology Platform, Warwick UniversityUniversité Paris Cité, NeuroDiderot, InsermSchool of Life Sciences, University of WarwickUniversité Paris Cité, NeuroDiderot, InsermWarwick Medical School, University of WarwickUniversité Paris Cité, Epigenetics and Cell Fate, CNRSUniversité Paris Cité, Epigenetics and Cell Fate, CNRSUniversité Paris Cité, NeuroDiderot, InsermAbstract Prenatal inflammatory insults accompany prematurity and provoke diffuse white matter injury (DWMI), which is associated with increased risk of neurodevelopmental pathologies, including autism spectrum disorders. DWMI results from maturation arrest of oligodendrocyte precursor cells (OPCs), a process that is poorly understood. Here, by using a validated mouse model of OPC maturation blockade, we provide the genome-wide ID card of the effects of neuroinflammation on OPCs that reveals the architecture of global cell fate issues underlining their maturation blockade. First, we find that, in OPCs, neuroinflammation takes advantage of a primed epigenomic landscape and induces abnormal overexpression of genes of the immune/inflammatory pathways: these genes strikingly exhibit accessible chromatin conformation in uninflamed OPCs, which correlates with their developmental, stage-dependent expression, along their normal maturation trajectory, as well as their abnormal upregulation upon neuroinflammation. Consistently, we observe the positioning on DNA of key transcription factors of the immune/inflammatory pathways (IRFs, NFkB), in both unstressed and inflamed OPCs. Second, we show that, in addition to the general perturbation of the myelination program, neuroinflammation counteracts the physiological downregulation of the cell cycle pathway in maturing OPCs. Neuroinflammation therefore perturbs cell identity in maturing OPCs, in a global manner. Moreover, based on our unraveling of the activity of genes of the immune/inflammatory pathways in prenatal uninflamed OPCs, the mere suppression of these proinflammatory mediators, as currently proposed in the field, may not be considered as a valid neurotherapeutic strategy.https://doi.org/10.1038/s41419-022-05483-4 |
| spellingShingle | Anne-Laure Schang Juliette Van Steenwinckel Zoi S. Ioannidou Julia Lipecki Charlotte Rich-Griffin Kate Woolley-Allen Nigel Dyer Tifenn Le Charpentier Patrick Schäfer Bobbi Fleiss Sascha Ott Délara Sabéran-Djoneidi Valérie Mezger Pierre Gressens Epigenetic priming of immune/inflammatory pathways activation and abnormal activity of cell cycle pathway in a perinatal model of white matter injury Cell Death and Disease |
| title | Epigenetic priming of immune/inflammatory pathways activation and abnormal activity of cell cycle pathway in a perinatal model of white matter injury |
| title_full | Epigenetic priming of immune/inflammatory pathways activation and abnormal activity of cell cycle pathway in a perinatal model of white matter injury |
| title_fullStr | Epigenetic priming of immune/inflammatory pathways activation and abnormal activity of cell cycle pathway in a perinatal model of white matter injury |
| title_full_unstemmed | Epigenetic priming of immune/inflammatory pathways activation and abnormal activity of cell cycle pathway in a perinatal model of white matter injury |
| title_short | Epigenetic priming of immune/inflammatory pathways activation and abnormal activity of cell cycle pathway in a perinatal model of white matter injury |
| title_sort | epigenetic priming of immune inflammatory pathways activation and abnormal activity of cell cycle pathway in a perinatal model of white matter injury |
| url | https://doi.org/10.1038/s41419-022-05483-4 |
| work_keys_str_mv | AT annelaureschang epigeneticprimingofimmuneinflammatorypathwaysactivationandabnormalactivityofcellcyclepathwayinaperinatalmodelofwhitematterinjury AT juliettevansteenwinckel epigeneticprimingofimmuneinflammatorypathwaysactivationandabnormalactivityofcellcyclepathwayinaperinatalmodelofwhitematterinjury AT zoisioannidou epigeneticprimingofimmuneinflammatorypathwaysactivationandabnormalactivityofcellcyclepathwayinaperinatalmodelofwhitematterinjury AT julialipecki epigeneticprimingofimmuneinflammatorypathwaysactivationandabnormalactivityofcellcyclepathwayinaperinatalmodelofwhitematterinjury AT charlotterichgriffin epigeneticprimingofimmuneinflammatorypathwaysactivationandabnormalactivityofcellcyclepathwayinaperinatalmodelofwhitematterinjury AT katewoolleyallen epigeneticprimingofimmuneinflammatorypathwaysactivationandabnormalactivityofcellcyclepathwayinaperinatalmodelofwhitematterinjury AT nigeldyer epigeneticprimingofimmuneinflammatorypathwaysactivationandabnormalactivityofcellcyclepathwayinaperinatalmodelofwhitematterinjury AT tifennlecharpentier epigeneticprimingofimmuneinflammatorypathwaysactivationandabnormalactivityofcellcyclepathwayinaperinatalmodelofwhitematterinjury AT patrickschafer epigeneticprimingofimmuneinflammatorypathwaysactivationandabnormalactivityofcellcyclepathwayinaperinatalmodelofwhitematterinjury AT bobbifleiss epigeneticprimingofimmuneinflammatorypathwaysactivationandabnormalactivityofcellcyclepathwayinaperinatalmodelofwhitematterinjury AT saschaott epigeneticprimingofimmuneinflammatorypathwaysactivationandabnormalactivityofcellcyclepathwayinaperinatalmodelofwhitematterinjury AT delarasaberandjoneidi epigeneticprimingofimmuneinflammatorypathwaysactivationandabnormalactivityofcellcyclepathwayinaperinatalmodelofwhitematterinjury AT valeriemezger epigeneticprimingofimmuneinflammatorypathwaysactivationandabnormalactivityofcellcyclepathwayinaperinatalmodelofwhitematterinjury AT pierregressens epigeneticprimingofimmuneinflammatorypathwaysactivationandabnormalactivityofcellcyclepathwayinaperinatalmodelofwhitematterinjury |