Epigenetic regulation of innate immune memory in microglia

Zhang, X.; Kracht, L.; Lerario, A. M.; Dubbelaar, M. L.; Brouwer, N.; Wesseling, E. M.; Boddeke, E.; Eggen, B. J. L.; Kooistra, S. M.

doi:10.1101/2021.05.30.446351

bioRxiv · 10.1101/2021.05.30.446351

Epigenetic regulation of innate immune memory in microglia

Zhang, X.·Kracht, L.·Lerario, A. M.·Dubbelaar, M. L.·Brouwer, N.·Wesseling, E. M.·Boddeke, E.·Eggen, B. J. L.·Kooistra, S. M.

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Abstract

Microglia are the tissue-resident macrophages of the CNS. They originate in the yolk sac, colonize the CNS during embryonic development and form a self-sustaining population with limited turnover. A consequence of their relative slow turnover is that microglia can serve as a long-term memory for inflammatory or neurodegenerative events. We characterized the epigenomes and transcriptomes of microglia exposed to different stimuli; an endotoxin challenge (LPS) and genotoxic stress (DNA repair deficiency-induced accelerated aging). Whereas the enrichment of permissive epigenetic marks at enhancer regions explains training (hyperresponsiveness) of primed microglia to LPS challenge, the tolerized response of microglia seems to be regulated by loss of permissive epigenetic marks. Here, we identify that inflammatory stimuli and accelerated aging because of genotoxic stress activate distinct gene networks. These gene networks and associated biological processes are partially overlapping, which is likely driven by specific transcription factor networks, resulting in altered epigenetic signatures and distinct functional (desensitized vs. primed) microglia phenotypes.

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Zhang, X., Kracht, L., Lerario, A. M., Dubbelaar, M. L., Brouwer, N., Wesseling, E. M., Boddeke, E., Eggen, B. J. L., Kooistra, S. M.. 2021-05-31. Epigenetic regulation of innate immune memory in microglia. https://doi.org/10.1101/2021.05.30.446351

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