A study published in Science (2017) reveals that the transcriptional identity of human microglia is highly dependent on the environment. Microglia, the resident macrophages of the central nervous system (CNS), play critical roles in maintaining CNS homeostasis and influencing neuronal function. However, the transcriptional mechanisms that define human microglia phenotypes remain poorly understood. The study examined the transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue and following transition to an in vitro environment. The results showed that transfer to a tissue culture environment leads to rapid and extensive downregulation of microglia-specific genes that are induced in primitive mouse macrophages upon migration into the fetal brain. These findings suggest that the brain environment significantly influences microglia gene expression and function. The study also identified a microglia-specific gene signature in the human brain, comprising 881 transcripts, which was enriched in various neurodegenerative and behavioral disorders. The microglia transcriptome was compared with that of mouse microglia, revealing overall similarities in gene expression patterns, with some species-specific differences. The study further demonstrated that the environment plays a critical role in shaping microglia identity and function, as microglia isolated from different individuals showed significant changes in gene expression when transferred to an in vitro environment. These changes included the downregulation of microglia-specific genes and the upregulation of genes associated with inflammation and stress responses. The study also identified that the transcriptional network controlling microglia identity is influenced by environmental factors, with the expression of key transcription factors such as PU.1, AP-1, and MEF2 being significantly affected by the environment. The study further showed that the microglia gene signature overlaps with genes that are up- and downregulated in Parkinson's disease, suggesting that changes in microglia gene expression reflect changes in the brain environment rather than changes in the microglia population. The study highlights the importance of the brain environment in shaping microglia function and its potential role in neurodegenerative and psychiatric diseases. The findings provide a critical resource for understanding the roles of microglia in human disease and for developing therapeutic strategies targeting microglia function.A study published in Science (2017) reveals that the transcriptional identity of human microglia is highly dependent on the environment. Microglia, the resident macrophages of the central nervous system (CNS), play critical roles in maintaining CNS homeostasis and influencing neuronal function. However, the transcriptional mechanisms that define human microglia phenotypes remain poorly understood. The study examined the transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue and following transition to an in vitro environment. The results showed that transfer to a tissue culture environment leads to rapid and extensive downregulation of microglia-specific genes that are induced in primitive mouse macrophages upon migration into the fetal brain. These findings suggest that the brain environment significantly influences microglia gene expression and function. The study also identified a microglia-specific gene signature in the human brain, comprising 881 transcripts, which was enriched in various neurodegenerative and behavioral disorders. The microglia transcriptome was compared with that of mouse microglia, revealing overall similarities in gene expression patterns, with some species-specific differences. The study further demonstrated that the environment plays a critical role in shaping microglia identity and function, as microglia isolated from different individuals showed significant changes in gene expression when transferred to an in vitro environment. These changes included the downregulation of microglia-specific genes and the upregulation of genes associated with inflammation and stress responses. The study also identified that the transcriptional network controlling microglia identity is influenced by environmental factors, with the expression of key transcription factors such as PU.1, AP-1, and MEF2 being significantly affected by the environment. The study further showed that the microglia gene signature overlaps with genes that are up- and downregulated in Parkinson's disease, suggesting that changes in microglia gene expression reflect changes in the brain environment rather than changes in the microglia population. The study highlights the importance of the brain environment in shaping microglia function and its potential role in neurodegenerative and psychiatric diseases. The findings provide a critical resource for understanding the roles of microglia in human disease and for developing therapeutic strategies targeting microglia function.