Transcriptional control of microglia phenotypes in health and disease

Abstract

Microglia are the main resident macrophage population of the CNS and perform numerous functions required for CNS development, homeostasis, immunity, and repair. Many lines of evidence also indicate that dysregulation of microglia contributes to the pathogenesis of neurodegenerative and behavioral diseases. These observations provide a compelling argument to more clearly define the mechanisms that control microglia identity and function in health and disease. In this Review, we present a conceptual framework for how different classes of transcription factors interact to select and activate regulatory elements that control microglia development and their responses to internal and external signals. We then describe functions of specific transcription factors in normal and pathological contexts and conclude with a consideration of open questions to be addressed in the future.

Figure 1. Enhancers and promoters interact to confer cell type–specific expression and response profiles.

Promoters are primarily occupied by general sequence-specific transcription factors (TFs), but are also important sites of action of lineage-determining TFs (LDTFs) and signal-dependent TFs (SDTFs). Enhancers are primarily selected by LDTFs and are usually the most numerous binding sites for SDTFs. External and internal signals converge on SDTFs to regulate enhancer and promoter function.

Figure 2. Different classes of transcription factors interact and regulate cellular identity.

The top of the figure illustrates the initial steps of enhancer selection in closed chromatin consisting of regularly positioned nucleosomes. Green and blue shading represents closely spaced binding sites for LDTFs. Below, collaborative interactions between LDTFs generate primed enhancers, characterized by a nucleosome-free region and monomethylated H3K4 (H3K4me1). At the bottom of the figure, active SDTFs localize to primed enhancers, resulting in recruitment of coactivators and RNA polymerase II and generation of enhancer RNAs (eRNAs).

Figure 3. Transcription factors that regulate different microglia phenotypes.

Microglia ontogeny is crucially dependent on LDTFs such as PU.1, MAFB, and SALL1 that are essential for the development of the ramified phenotype depicted in the center. Microglia are diverse cells that acquire different functional phenotypes in response to the environment in which they reside. Several transcriptional regulators have been identified that regulate different microglia phenotypes. For example, proinflammatory microglia are regulated by IRF7, RelA, STAT1/3, and FosB. Microglia that mediate neuropathic pain are induced by expression of Irf1, Irf5, and Irf8 in microglia. Microglia that contribute to HIV-associated neurodegeneration are characterized by an induction of p53. Figure adapted with permission from Nature Reviews Neurology (128).