An environment-dependent transcriptional network regulates human microglia phenotypes

Microglia play essential roles in central nervous system (CNS) homeostasis and influence diverse aspects of neuronal function. Although dysregulation of microglia activity is genetically linked to neurodegenerative and behavioral diseases, the transcriptional mechanisms that specify human microglia phenotypes are largely unknown. We report here on the transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue, revealing broad similarities but also significant differences with mouse microglia. Many genes associated with risk alleles for neurodegenerative diseases are preferentially or highly expressed in human microglia. The transition of human and mouse microglia from the brain to a tissue culture environment results in rapid and extensive downregulation of genes that are induced in primitive mouse macrophages following migration into the fetal brain. These findings reveal an environment-dependent transcriptional network specifying microglia-specific programs of gene expression and will facilitate efforts to better understand the roles of microglia in human disease. We isolated microglia ex vivo from mouse brains using FACS. We also cultured isolated mouse microglia in vitro for varying lengths of time, both with and without TGFB. Various subsets of these cells were assayed with RNA-seq, ATAC-seq, as well as ChIP-seq for the transcription factor PU.1 and the histone marks H3K4me2 and H3K27ac.