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<jats:title>Abstract</jats:title><jats:p>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.</jats:p><jats:sec><jats:title>Significance statement</jats:title><jats:p>Neuroinflammation provokes premature birth, the commonest cause of death and disability in children, including autism. Neuroinflammation-induced neurological damage encompasses white matter injury. The actual therapeutic strategies are orientated towards global repression of proinflammatory actors. We explore the epigenomic and transcriptomic impacts of neuroinflammation on a purified cell population of oligodendrocyte precursors cells (OPCs). 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, in particular that of the inflammatory pathway. These proinflammatory genes are constitutively expressed by OPCs and their physiological downregulation during OPC maturation process is counteracted by neuroinflammation. The intricacy between the OPC physiological and neuroinflammation-responsive expression of these proinflammatory mediators reorientates neuroprotective strategies.</jats:p></jats:sec>

Original publication

DOI

10.1101/411702

Type

Journal article

Publisher

Cold Spring Harbor Laboratory

Publication Date

19/10/2018