Epigenome priming dictates transcription response and white matter fate upon perinatal inflammation

Abstract

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. Schang et al. 2 Author's contributions ALS performed bioinformatics microarray and ATAC--seq dataset analyses, as well as wet experiments, including the MACS--isolation of O4+ OPCs and RT--qPCR experiments, in association with JvS (experimental design, mouse treatment and cell sorting) and TLC (cell culture, cytokine quantification by luminex). BF contributed to the design of the project, and brought very helpful suggestions along the experimental process and writing of manuscript. SO, DSD, PG and VM codirected the work. SO supervised JL, CRG, KWA and ND in their input ATAC--seq analyses and developed bioinformatic tools for testing for enrichment of paired motifs of transcription binding sites, and also proposed and performed the bioinformatic comparison between the epigenomic landscapes of OPCs and inflamed HAECs. PS co--supervised JL and CRG. DSD played a major role in suggesting the use of ATAC--Seq, animated the collaboration with SO, and performed the MACs--isolation of OPCs and ATAC--Seq data experiments with ALS whom she co--supervised with VM and PG. PG scientifically co--directed with VM the project. In particular, he was at the origin of the MACS--isolation of the OPCs and produced OPC transcriptomic datasets and initiated their analyses. VM drove the study by proposing to analyze and intersect epigenomic data and transcriptomic data, for which she supervised DSD and co--supervised ALS; she wrote the paper with input from ALS, BF, SO, DSD, and PG. Schang et al. 3 AbstractPremature 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--depen...

Immediate perturbations of DNA methylation and transcriptome upon acute prenatal alcohol exposure in the mouse developing brain cortex

“…However, we also observe that the triplicates of the EtOH-treated group show more differences between each other than do triplicates from the control group. Interestingly, this is also observed in another paradigm prenatal stress due to neuroinflammation between samples within the exposed group (Schang et al, 2018a), and more generally the exacerbated cell-to-cell variability provoked by PAE (Ishii et al, 2017). Indeed, this might reflect the immediate impact of cellular stress caused by ethanol exposure, and the disequilibrium, with some stochastic aspects, it imposes to cellular functions and molecular pathways, including the regulation of DNA methylation, before the system reaches a new equilibrium.…”

“… (A) Number of regions in each methylome capture category. “Other regions” correspond to HSF2 genome-wide occupancy, a stress-responsive transcription factor involved in FASD phenotypes (El Fatimy et al, 2014; ChIP-seq data), and to differentially accessible regions and H3K4me1-marked enhancer regions associated to gene differentially expressed in response to another prenatal stress, neuroinflammation (Schang et al, 2018a; Krishnan et al, 2017, GSE197563; see Materials and Methods). Note that categories are not exclusive ( i.e.…”

“…The prenatal developing brain is particularly vulnerable to detrimental events that generate neurodevelopmental defects and potentially have long-term consequences in the adulthood (Bale et al, 2010; Schang et al, 2018a). Among a diversity of adverse in utero stresses, prenatal alcohol exposure (PAE) is a leading cause of non-genetic mental retardation in the Western world (Popova et al, 2012, 2016).…”