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bioRxiv · 10.1101/411702

Discordant perturbations of transcriptome and epigenome landscapes highlight dual roles of proinflammatory players in normal and IL1B-compromised OPC maturation trajectory in a prenatal model of diffuse white matter injury

Schang, A.-L.·van Steenwinckel, J.·Lipecki, J.·Rich, C.·Woolley-Allen, K.·Dyer, N.·Le Charpentier, T.·Fleiss, B.·Schafer, P.·Ott, S.·Mezger, V.·Saberan-Djoneidi, D.·Gressens, P.
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Abstract

Inflammatory insults accompanying prematurity provokes diffuse white matter injury (DWMI) which is associated with increased risk of neurodevelopmental disorders: pre-term infants have a 10 to 18-fold increased risk of developing autism spectrum disorders, compared to term infants. DWMI is due to maturation arrest in oligodendrocyte precursor cells (OPCs). Using integrated genome-wide approaches in a validated mouse perinatal model of DWMI, induced by systemic- and neuro-inflammation based on repeated interleukin-1B administrations, we show that neuroinflammation induces limited epigenomic disturbances in OPCs. In contrast, we unravel marked transcriptomic alterations of genes of the immune/inflammatory pathways, which are expressed in unstressed OPCs and physiologically downregulated along OPC maturation. Consistently, we observe that transcription factors of the inflammatory pathways occupy 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. Therefore, our study opens new avenues for the future development of targeted approaches to protect preterm brains. Highlights{circ} Limited epigenomic impact of inflammation on OPC maturation blockade {circ}Major transcriptomic disturbances take advantage of a primed epigenetic landscape {circ}Proinflammatory genes are active in OPCs and downregulated upon maturation {circ}Neuroinflammation counteracts both this downregulation and maturation in OPCs

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Schang, A.-L., van Steenwinckel, J., Lipecki, J., Rich, C., Woolley-Allen, K., Dyer, N., Le Charpentier, T., Fleiss, B., Schafer, P., Ott, S., Mezger, V., Saberan-Djoneidi, D., Gressens, P.. 2018-10-18. Discordant perturbations of transcriptome and epigenome landscapes highlight dual roles of proinflammatory players in normal and IL1B-compromised OPC maturation trajectory in a prenatal model of diffuse white matter injury. https://doi.org/10.1101/411702

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