Journal Article

An environment-dependent transcriptional network specifies human microglia identity

Jaeger, Baptiste N., Glass, Christopher K., Gonda, David D., Gage, Fred H., Holtman, Inge R., Sajti, Eniko, Schlachetzki, Johannes C. M., Adair, Amy, Skola, Dylan, Levy, Michael L., Fitzpatrick, Conor, Pena, Monique, Gosselin, David, Ransohoff, Richard M., Coufal, Nicole G., O’Connor, Carolyn, Pasillas, Martina P.

2017

Overview

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. Science , this issue p. eaal3222 Single-cell sequencing of brain microglia reveals ex vivo and in vitro differences in transcription. 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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Age Differences / Alleles / Alzheimer's disease / Anatomy / Animal models / Animals / Behavior disorders / Brain / Brain Neoplasms - genetics / Brain Neoplasms - physiopathology / Cell culture / Cells, Cultured / Central nervous system / Chromatin / Delineation / Deoxyribonucleic acid / Diagnosis / Diseases / Disorders / DNA / Environment / Epigenetics / Epilepsy - genetics / Epilepsy - physiopathology / Female / Fetuses / Gene expression / Gene Expression Profiling / Gene Expression Regulation / Gene regulation / Gene Regulatory Networks - physiology / Gene sequencing / Genes / Genome-wide association studies / Genomes / Genotype-environment interactions / Growth factors / Health risks / Homeostasis / Humans / Immune system / In vitro testing / Influence / Learning / Macrophages / Male / Memory / Mental depression / Mental disorders / Mice / Mice, Inbred C57BL / Microglia / Microglia - cytology / Microglia - physiology / Movement disorders / Nervous system / Networks / Neurodegenerative diseases / Neuromodulation / Parkinson's disease / Pathogenesis / Psychiatry / Purification / RESEARCH ARTICLE SUMMARY / Ribonucleic acid / Risk / RNA / Schizophrenia / Surgery / Tissue culture / Tissues / Transcription factors / Transforming growth factor-b1