Summary
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
∘ Limited epigenomic impact of inflammation on OPC maturation blockade
∘ Major transcriptomic disturbances take advantage of a primed epigenetic landscape
∘ Proinflammatory genes are active in OPCs and downregulated upon maturation
∘ Neuroinflammation counteracts both this downregulation and maturation in OPCs
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵$ Lead contact: valerie.mezger{at}u-paris.fr
FUNDING Information VM was funded by CNRS, Université Paris Diderot, Agence Nationale de la Recherche (« HSF-EPISAME », SAMENTA ANR-13-SAMA-0008-01) and FRA 2015/16. DSD was funded by Paris Diderot University for travel grant for SO. ALS was supported by a postdoctoral fellowship by SAMENTA ANR-13-SAMA-0008-01. PG was funded by Inserm, Université Paris Diderot, ANR-13-SAMA-0008-01, Fondation Grace de Monaco, PremUP, Fondation des Gueules Cassées, ARSEP, and an additional grant from “Investissement d’Avenir -ANR-11-INBS-0011-” NeurATRIS. BF acknowledges support from Cerebral Palsy Alliance, Australia. PG and BF acknowledge financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. JL, CR, and KWA were funded by the Biotechnology and Biological Sciences Research Council (UK) through the Midlands Integrative Biology Training Partnership (MIBTP). The supporting bodies played no role in any aspect of study design, analysis, interpretation or decision to publish this data.
Declaration of interests The authors declare no competing interests.
This version has been updated in order to addd some new experiments and in order to precise Authors affiliation, give a clearer title and correct some typos errors. Some supplemental tables have been added
