Chromatin accessibility in oligodendrocyte precursors profiled by ATAC-seq: Neuroprotective effects of MgSO4 and 4-PBA alone or associated in a mouse model of encephalopathy of prematurity

Cerebral palsy (CP) is the leading cause of motor disability in children. Hypoxia-ischemia (HI) and prematurity are main risk factors. Administration of magnesium sulfate (MgSO4) to mothers before 33 weeks' amenorrhea (SA) reduces the occurrence of CP at 2 years by around 30%. At this age, the white matter composed by oligodendrocytes, is particularly vulnerable. However, at long term, MgSO4 neuroprotective effects are not significant.Given the anti-inflammatory and antioxidant properties of 4-phenylbutyrate (4-PBA), its association with MgSO4 may optimize and prolong this neuroprotection in preterms.Using a murine model of neonatal HI in postnatal day 5 pups, it has been shown that the association of MgSO4 with 4-PBA provides an increased and prolonged protection.Because of the histone deacetylase inhibitory action of 4-PBA, the potential epigenetic mechanisms underlying this neuroprotection were investigated.Adapted from the Rice Vannuci model, P5 NMRI mice underwent left carotid ligation and hypoxia (45 min at 8% O2). On the same day, they received MgSO4 (600 mg/kg, intraperitoneal (i.p).) and 4-PBA (600 mg/kg, i.p). Targeting oligodendrocyte precursors, the epigenetic effects of HI and treatments were assessed by ATACseq.Detection of differentially accessible genomic regions between conditions enabled to generate a map of the targets of HI and treatments epigenetic effects in pre-oligodendrocytes.This technic allows to identify, without a priori, unknown genomic regions potentially involved in the enhanced neuroprotection of MgSO4 when associated with 4-PBA.