Enhancer-associated epigenetic signatures define microglia immune responses Zhang X1*, Kooistra SM1*, Dubbelaar ML1, Lerario A2, Kracht L1, Brouwer N1, Boddeke HWGM1, Eggen BJL1 1Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands; 2Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, Michigan, USA *These authors contributed equally
Microglia are the macrophages of the CNS with innate and adaptive immune functions. Microglia, like other innate immune cells, have the potential to serve as a memory for past inflammatory events, similar to endotoxin tolerance and trained immunity in macrophages. We previously showed that microglia display a dampened immune response to a secondary endotoxin stimulus. On the opposite end of the spectrum, an enhanced response to LPS treatment is observed in a mouse model for accelerated ageing, lacking the nucleotide excision repair gene Ercc1.
Here we used in vivo LPS treatment of wild type and Ercc1 mutant mice to induce alterations in microglia functionality. Microglia were isolated from the CNS by FACS sorting (CD11b+, CD45+, Ly6C-) and subsequently we performed genome-wide RNA expression profiling, ChIP- and ATAC-sequencing. Combinatorial analysis of modified histones, open chromatin and gene expression changes was used to identify the molecular mechanisms and relevant genomic regions underlying these opposing functional microglia phenotypes.
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