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

Premature birthis the commonest cause of death and disability in children under 5 years of age. Diffuse white matter injury (DWMI) is one of the hallmarks of neurological damages associated to premature birth, and is associated with increased risk of autism spectrum disorders. DWMI is due to maturation arrest in oligodendrocyte precursors (OPCs), consequently leads to cortical hypomyelination, and is provoked by inflammatory insults accompanying premature birth. The lack of therapeutic solutions is a strong hint to unveil the molecular mechanisms underlying the persistent impact of neuroinflammationon OPC cell fate. We took advantage of a validated mouse model of DWMI, based on interleukin 1B (IL1B) intraperitoneal administration from postnatal days 1 to 5 (P1-P5), which recapitulates OPCs maturational arrest. Using integrated genome-wide approaches, we challenged the robustness versus vulnerability of epigenomeand transcriptome at the end of IL1B exposure, in a purified population of premyelinating OPCs. We evidenced limited epigenomicdisturbances in ILB1-treated OPCs, but, in contrast, marked transcriptomic alterations, linked to abnormally sustained activation of immune/inflammatory and corresponding transcription factor pathways. These genes are indeed expressed in unstressed OPCs and we show that they are physiologically downregulated along the normal P0-P5 developmental OPC trajectory. Rather than provoking major changes in genome-wide chromatin accessibility, neuroinflammationtakes advantage of open chromatin regions and active transcriptional programs at the time of exposure, and deeply counteracts their stage-dependent regulation by sustained upregulation of their transcript levels. The same transcription factors are not only involved in the stress-responsive upregulation of target genes of the immune/inflammatory pathways in OPC exposed to IL1B, but also in the expression of the same inflammatory players in unstressed OPCs, during their normal stage-dependent maturation. The encounter of their potential developmental role in OPC trajectory and their stress-responsive action upon ILB1 exposure paves the way for intricate interference between the response to neuroinflammatory insults and the white matter developmental program, likely contributing to OPC maturation arrest.