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Sequential changes in histone modifications shape transcriptional responses underlying microglia polarization by glioma
Author(s) -
Maleszewska Marta,
Steranka Aleksandra,
Smiech Magdalena,
Kaza Beata,
Pilanc Paulina,
Dabrowski Michal,
Kaminska Bozena
Publication year - 2021
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23887
Subject(s) - microglia , biology , histone , epigenetics , chromatin , gene silencing , epigenetic regulation of neurogenesis , chromatin immunoprecipitation , glioma , microbiology and biotechnology , neuroscience , cancer research , gene expression , inflammation , immunology , gene , chromatin remodeling , genetics , promoter
Microglia, resident myeloid cells of the central nervous system (CNS), act as immune sentinels that contribute to maintenance of physiological homeostasis and respond to any perturbation in CNS. Microglia could be polarized by various stimuli to perform dedicated functions and instigate inflammatory or pro‐regenerative responses. Microglia and peripheral macrophages accumulate in glioblastomas (GBMs), malignant brain tumors, but instead of initiating antitumor responses, these cells are polarized to the pro‐invasive and immunosuppressive phenotype which persists for a long time and contributes to a “cold” immune microenvironment of GBMs. Molecular mechanisms underlying this long‐lasting “microglia memory” are unknown. We hypothesized that this state may rely on epigenetic silencing of inflammation‐related genes. In this study, we show that cultured microglia pre‐exposed to glioma‐conditioned medium (GCM) acquire a “transcriptional memory” and display reduced expression of inflammatory genes after re‐stimulation with lipopolysaccharide. Unstimulated microglia have unmethylated DNA and active histone marks at selected gene promoters indicating chromatin accessibility. Adding GCM increases expression and enzymatic activity of histone deacetylases (Hdac), leading to erasure of histone acetylation at tested genes. Later inflammatory genes acquire repressive histone marks (H3K27 trimethylation), which correlates with silencing of their expression. GCM induced genes acquire active histone marks. Hdac inhibitors block GCM‐induced changes of histone modifications and restore microglia ability to initiate effective inflammatory responses. Altogether, we show a scenario of distinct histone modifications underlying polarization of microglia by glioma. We demonstrate contribution of epigenetic mechanisms to glioma‐induced “transcriptional memory” in microglia resulting in the tumor‐supportive phenotype.