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Pré-Publication, Document De Travail Année : 2019

Epigenome and transcriptome landscapes highlight dual roles of proinflammatory players in a perinatal model of white matter injury

Patrick Schäfer
  • Fonction : Auteur

Résumé

Premature birth is the commonest cause of death and disability in young children. Diffuse white matter injury (DWMI), provoked by inflammatory insults accompanying prematurity, is associated with increased risk of neurodevelopmental disorders – such as autism spectrum disorders – and is due to maturation arrest in oligodendrocyte precursors (OPCs). The lack of therapeutic solutions is a strong impetus to unveil the molecular mechanisms underlying neuroinflammation impact on OPC cell fate. We used a validated mouse model of DWMI, induced by systemic- and neuro-inflammation – as observed in preterm infants – and based on interleukin-1B administration from postnatal day P1 to P5. Using integrated genome-wide approaches we showed that neuroinflammation induced limited epigenomic disturbances in OPCs, but marked transcriptomic alterations of genes of the immune/inflammatory pathways. We found that these genes were expressed in control OPCs and physiologically downregulated between P3-P10, as part of the OPC normal developmental trajectory. We observed that transcription factors of the inflammatory pathways occupied DNA both in unstressed and inflamed OPCs. Thus, rather than altering genome-wide chromatin accessibility, neuroinflammation takes advantage of open chromatin regions and deeply counteracts the stage-dependent downregulation of these active transcriptional programs by the sustained upregulation of transcript levels. The intricate dual roles – stress-responsive and potentially developmental – of these proinflammatory mediators strongly suggest that the mere suppression of these inflammatory mediators, as currently proposed, may not be a valid neurotherapeutic strategy. Our study provides new insights for the future development of more targeted approaches to protect the preterm brain.
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Dates et versions

hal-02414279 , version 1 (16-12-2019)

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Anne--Laure Schang, Juliette van Steenwinckel, Julia Lipecki, Charlotte Rich--Griffin, Kate Woolley--Allen, et al.. Epigenome and transcriptome landscapes highlight dual roles of proinflammatory players in a perinatal model of white matter injury. 2019. ⟨hal-02414279⟩
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