Epigenetics Control Microglia Plasticity

Abstract

Microglia, resident immune cells of the central nervous system, fulfill multiple functions in the brain throughout life. These microglial functions range from participation in innate and adaptive immune responses, involvement in the development of the brain and its homeostasis maintenance, to contribution to degenerative, traumatic, and proliferative diseases; and take place in the developing, the aging, the healthy, or the diseased brain. Thus, an impressive level of cellular plasticity, appears as a requirement for the pleiotropic biological functions of microglia. Epigenetic changes, including histone modifications or DNA methylation as well as microRNA expression, are important modifiers of gene expression, and have been involved in cell phenotype regulation and reprogramming and are therefore part of the mechanisms regulating cellular plasticity. Here, we review and discuss the epigenetic mechanisms, which are emerging as contributors to this microglial cellular plasticity and thereby can constitute interesting targets to modulate microglia associated brain diseases, including developmental diseases, neurodegenerative diseases as well as cancer.

Keywords: DNA methylation; epigenetics; histone post-translational modification; microglia; non-coding RNAs.

FIGURE 1

Histone modifications occurring upon microglia polarization. (A) Post-translational modifications on histone tails that occur in microglia are represented. These covalent modifications are added or removed by histone modifying enzymes often referred as writers and erasers. (B) Positive or negative correlation for the expression levels of these histone modifications or the enzymes regulating those histone marks with the polarization toward so-called “M1” or “M2” microglia phenotypes are reported. Ac, Acetylated; me, methylated.

FIGURE 2

Epigenetic control of microglia. Illustration of the importance for epigenetics mechanisms for the acquisition of microglia activation states in response to various stimuli (A), for the definition of unique microglial molecular signatures throughout life, including microglia development and aging (the different microglia colors represents the different phenotypes these cells can harbor like pro-inflammatory/wound healing/pro-tumoral phenotypes among others) (B), as well as for the long-lasting effect observed on microglia phenotypes such as in the context of microglial priming (C) or upon maternal immune activation (D).