Abstract
Microglia are resident immune cells in the central nervous system (CNS). Microglia exhibit diversity in their morphology, density, electrophysiological properties, and gene expression profiles, and play various roles in neural development and adulthood in both physiological and pathological conditions. Recent transcriptomic analysis using bulk and single-cell RNA-seq has revealed that microglia can shift their gene expression profiles in various contexts, such as developmental stages, aging, and disease progression in the CNS, suggesting that the heterogeneity of microglia may be associated with their distinct functions. Epigenetic changes, including histone modifications and DNA methylation, coordinate gene expression, thereby contributing to the regulation of cellular state. In this review, we summarize the current knowledge regarding the epigenetic mechanisms underlying spatiotemporal and functional diversity of microglia that are altered in response to developmental stages and disease conditions. We also discuss how this knowledge may lead to advances in therapeutic approaches for diseases.
Highlights
Microglia are immune cells that have been studied extensively for their roles in pathological conditions
A series of molecular techniques based on ChromosomeConformation-Capture (3C), including 4C, 5C, and Hi-C, have been used to analyze the spatial organization of chromatin (Dekker et al, 2002; de Wit and de Laat, 2012). These methods enable the quantification of chromatin-chromatin interactions at different scales: 3C quantifies the interactions between two specific DNA fragments using PCR, whereas Hi-C quantifies the interactions between all possible pairs of fragments using paired end sequencing. These techniques have revealed that hierarchically organized spatial chromatin architecture is crucial for the regulation of gene transcription, which in turn is essential for the development and maintenance of various biological processes and epigenetic profiles of the linear genome such as histone modifications and DNA methylation (Phillips-Cremins, 2014)
Comparison of disease-associated microglia (DAM) enhancers in wildtype (WT) and 5xfamilial AD (5xFAD) mice using a high sensitivity method for ChIP-seq analysis (Lara-Astiaso et al, 2014) revealed a similar level of H3K4me2, which marks promoter and enhancer regions (Keren-Shaul et al, 2017). These findings suggest that the disease-associated regions primed in DAM are already primed in homeostatic microglia
Summary
Edited by: Raghuveer Kavarthapu, National Institutes of Health (NIH), United States. Specialty section: This article was submitted to Signaling, a section of the journal Frontiers in Cell and Developmental. Microglia are resident immune cells in the central nervous system (CNS). Microglia exhibit diversity in their morphology, density, electrophysiological properties, and gene expression profiles, and play various roles in neural development and adulthood in both physiological and pathological conditions. Recent transcriptomic analysis using bulk and single-cell RNA-seq has revealed that microglia can shift their gene expression profiles in various contexts, such as developmental stages, aging, and disease progression in the CNS, suggesting that the heterogeneity of microglia may be associated with their distinct functions. Epigenetic changes, including histone modifications and DNA methylation, coordinate gene expression, thereby contributing to the regulation of cellular state. We summarize the current knowledge regarding the epigenetic mechanisms underlying spatiotemporal and functional diversity of microglia that are altered in response to developmental stages and disease conditions.
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