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Series GSE166075 Query DataSets for GSE166075
Status Public on Jan 28, 2022
Title A primed immune transcriptional program is activated in oligodendroglia in multiple sclerosis [Cut&Run EZH2i]
Organism Mus musculus
Experiment type Other
Summary Multiple sclerosis (MS) is a disease characterized by a targeted immune attack on myelin in the central nervous system (CNS). We have previously shown that oligodendrocytes (OLs), myelin producing cells in the CNS, and their precursors (OPCs), acquire disease-specific transcriptional states in MS. To understand how these alternative transcriptional programs are activated in disease, we performed single-cell assay for transposase accessible chromatin using sequencing (scATAC-seq) on the OL lineage in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We identified regulatory regions with increased accessibility in oligodendroglia (OLG) in EAE, some of which in the proximity of immune genes. A similar remodeling of chromatin accessibility was observed upon treatment of postnatal OPCs with interferon-gamma (IFNg), but not with dexamethasone. These changes in accessibility were not exclusive to distal enhancers, but also occurred at promoter regions, suggesting a role for promoters in mediating cell-state transitions. Notably, we found that a subset of immune genes already exhibited chromatin accessibility in OPCs ex vivo and in vivo, suggesting a primed chromatin state in OLG compatible with rapid transitions to an immune-competent state. Several primed genes presented bivalency of H3K4me3 and H3K27me3 at promoters in OPCs, with loss of H3K27me3 upon IFNg treatment. Inhibition of JMJD3/KDM6B, mediating removal of H3K27me3, led to the inability to activate these genes upon IFNg treatment. Importantly, OLGs from the adult human brain showed chromatin accessibility at immune gene loci, particularly at MHC-I pathway genes. A subset of single-nucleotide polymorphisms (SNPs) associated with MS susceptibility overlapped with these primed regulatory regions in OLG from both mouse and human CNS. Our data suggest that susceptibility for MS may involve activation of immune gene programs in OLG. These programs are under tight control at the chromatin level in OLG and may therefore constitute novel targets for immunological-based therapies for MS.
Overall design We have performed bulk CUT&RUN for H3K27ac, H3K27me3 and H3K4me3 from FACS sorted Sox10GFP+ oligodendrocyte precursor cells treated with EZH2 inhibitor. After 4 days IFN-gamma was added together with new EZH2 inhibitor. 
Contributor(s) Meijer M, Agirre E, Kabbe M, van Tuijn CA, Heskol A, Falcao AM, Corces MR, Montine TJ, Chen X, Chang HY, Castelo-Branco G
Citation(s) 35093191
Submission date Feb 03, 2021
Last update date Apr 29, 2022
Contact name Eneritz Agirre
Organization name Karolinska Institutet
Department MBB
Lab Castelo-Branco, Molecular Neurobiology
Street address Solnavägen 9
City Stockholm
ZIP/Postal code 17165
Country Sweden
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (24)
GSM5061465 H3K4me3_Ctr_Ezh2i_0uM_rep1
GSM5061466 H3K4me3_IFNg_Ezh2i_0uM_rep1
GSM5061467 H3K4me3_Ctr_Ezh2i_1.5uM_rep1
BioProject PRJNA699226
SRA SRP304517

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Supplementary file Size Download File type/resource
GSE166075_Ctr_0Ezh2i_H3K27ac_dupmark.bam_peaks.broadPeak.gz 148.6 Kb (ftp)(http) BROADPEAK
GSE166075_Ctr_0Ezh2i_H3K27me3_dupmark.bam_peaks.broadPeak.gz 115.9 Kb (ftp)(http) BROADPEAK
GSE166075_Ctr_0Ezh2i_H3K4me3_dupmark.bam_peaks.broadPeak.gz 596.6 Kb (ftp)(http) BROADPEAK
GSE166075_Ctr_15Ezh2i_H3K27ac_dupmark.bam_peaks.broadPeak.gz 4.5 Kb (ftp)(http) BROADPEAK
GSE166075_Ctr_15Ezh2i_H3K27me3_dupmark.bam_peaks.broadPeak.gz 86.9 Kb (ftp)(http) BROADPEAK
GSE166075_Ctr_15Ezh2i_H3K4me3_dupmark.bam_peaks.broadPeak.gz 632.1 Kb (ftp)(http) BROADPEAK
GSE166075_IFNg_0Ezh2i_H3K27ac_dupmark.bam_peaks.broadPeak.gz 75.3 Kb (ftp)(http) BROADPEAK
GSE166075_IFNg_0Ezh2i_H3K27me3_dupmark.bam_peaks.broadPeak.gz 112.6 Kb (ftp)(http) BROADPEAK
GSE166075_IFNg_0Ezh2i_H3K4me3_dupmark.bam_peaks.broadPeak.gz 499.5 Kb (ftp)(http) BROADPEAK
GSE166075_IFNg_15Ezh2i_H3K27ac_dupmark.bam_peaks.broadPeak.gz 3.5 Kb (ftp)(http) BROADPEAK
GSE166075_IFNg_15Ezh2i_H3K27me3_dupmark.bam_peaks.broadPeak.gz 125.1 Kb (ftp)(http) BROADPEAK
GSE166075_IFNg_15Ezh2i_H3K4me3_dupmark.bam_peaks.broadPeak.gz 614.4 Kb (ftp)(http) BROADPEAK
GSE166075_RAW.tar 2.5 Gb (http)(custom) TAR (of WIG)
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Raw data are available in SRA
Processed data provided as supplementary file
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