Research Article

An environment-dependent transcriptional network specifies human microglia identity

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Science  23 Jun 2017:
Vol. 356, Issue 6344, eaal3222
DOI: 10.1126/science.aal3222

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Of mice and men's microglia

Microglia are immune system cells that function in protecting and maintaining the brain. Gosselin et al. examined the epigenetics and RNA transcripts from single microglial cells and observed consistent profiles among samples despite differences in age, sex, and diagnosis. Mouse and human microglia demonstrated similar microglia-specific gene expression profiles, as well as a shared environmental response among microglia collected either immediately after surgery (ex vivo) or after culturing (in vitro). Interestingly, those genes exhibiting differences in expression between humans and mice or after culturing were often implicated in neurodegenerative diseases.

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Structured Abstract

INTRODUCTION

Microglia play essential roles in central nervous system homeostasis and influence diverse aspects of neuronal function, including refinement of synaptic networks and elaboration of neuromodulatory factors for memory and motor learning. Many lines of evidence indicate that dysregulation of microglial functions contributes to the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Emerging evidence from mouse and human studies also suggests that microglia influence neurodevelopmental and psychiatric disorders such as schizophrenia and depression. Most disease risk alleles associated with neurodegenerative diseases reside in noncoding regions of the genome, requiring the delineation of functional genomic elements in the relevant human cell types to establish mechanisms of causation. The recent observation that mouse brain environment strongly influences microglia-specific gene expression has implications for understanding pathogenic responses of microglia in diseases and disorders and modeling their phenotypes in vitro.

RATIONALE

Although dysregulation of microglial activity is genetically linked to neurodegenerative diseases and psychiatric disorders, no systematic evaluations of human microglia gene expression or regulatory landscapes are currently available. In addition, the extent to which mice provide suitable models for human microglia is unclear. The major goals of this study were to define the transcriptomes and DNA regulatory elements of human microglia ex vivo and in vitro in comparison to the mouse and to systematically relate these features to expression of genes associated with genome-wide association study (GWAS) risk alleles or exhibiting altered expression in neurodegenerative diseases and psychiatric disorders.

RESULTS

We used RNA sequencing, chromatin immunoprecipitation sequencing, and assay for transposase-accessible chromatin sequencing to characterize the transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue in excess of that needed for diagnosis. Although some effects of underlying disease cannot be excluded, the overall pattern of gene expression was markedly consistent. Microglia-enriched genes were found to overlap significantly with genes exhibiting altered expression in neurodegenerative diseases and psychiatric disorders and with genes associated with a wide spectrum of disease-specific risk alleles. Human microglia gene expression was well correlated with mouse microglia gene expression, but numerous species-specific differences were also observed that included genes linked to human disease. More than half of the genes associated with noncoding GWAS risk alleles for Alzheimer’s disease are preferentially expressed in microglia. DNA recognition motifs enriched at active enhancers and expression of the corresponding lineage-determining transcription factors were very similar for human and mouse microglia. Transition of human and mouse microglia from the brain to tissue culture revealed remodeling of their respective enhancer landscapes and extensive down-regulation of genes that are induced in primitive mouse macrophages following migration into the fetal brain. Treatment of microglia in vitro with transforming growth factor β1 (TGF-β1) had relatively modest effects in maintaining the ex vivo pattern of gene expression. A significant subset of the genes up- or down-regulated in vitro exhibited altered expression in neurodegenerative diseases and psychiatric disorders.

CONCLUSION

These studies identify core features of human microglial transcriptomes and epigenetic landscapes. Intersection of the microglia-specific gene signature with GWAS and transcriptomic data supports roles of microglia as both responders and contributors to disease phenotypes. The identification of an environment-sensitive program of gene expression and corresponding regulatory elements enables inference of a conserved and dynamic transcription factor network that maintains microglia identity and function. The combinations of signaling factors in the brain necessary to maintain microglia phenotypes remain largely unknown. In concert, these findings will inform efforts to generate microglia-like cells in simple and complex culture systems and understand gene-environment interactions that influence homeostatic and pathogenic functions of microglia in the human brain.

Brain environment specifies gene expression in microglia.

Human microglia transcriptomes and enhancer landscapes were defined ex vivo following purification from surgically resected brain tissue and in vitro after transfer to a tissue culture environment. Dynamic changes in these features enabled delineation of transcription factors controlling an environment-dependent program of gene expression that overlaps with genes that are dysregulated in brain pathologies.

Abstract

Microglia play essential roles in central nervous system (CNS) homeostasis and influence diverse aspects of neuronal function. However, the transcriptional mechanisms that specify human microglia phenotypes are largely unknown. We examined the transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue ex vivo and after transition to an in vitro environment. Transfer to a tissue culture environment resulted in rapid and extensive down-regulation of microglia-specific genes that were induced in primitive mouse macrophages after migration into the fetal brain. Substantial subsets of these genes exhibited altered expression in neurodegenerative and behavioral diseases and were associated with noncoding risk variants. These findings reveal an environment-dependent transcriptional network specifying microglia-specific programs of gene expression and facilitate efforts to understand the roles of microglia in human brain diseases.

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