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An environment-dependent transcriptional network specifies human microglia identity.

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.

SUBMITTER: Gosselin D

PROVIDER: S-EPMC5858585 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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An environment-dependent transcriptional network specifies human microglia identity.

Gosselin David D Skola Dylan D Coufal Nicole G NG Holtman Inge R IR Schlachetzki Johannes C M JCM Sajti Eniko E Jaeger Baptiste N BN O'Connor Carolyn C Fitzpatrick Conor C Pasillas Martina P MP Pena Monique M Adair Amy A Gonda David D DD Levy Michael L ML Ransohoff Richard M RM Gage Fred H FH Glass Christopher K CK

Science (New York, N.Y.) 20170525 6344

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 ...[more]

PMID: 28546318

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Project description:Microglia are the tissue-resident macrophages of the retina and brain, being critically involved in organ development, tissue homeostasis, and response to cellular damage. Until now, little is known about the transcriptional profile of human retinal microglia and how they differentiate from peripheral monocytes, as well as from brain microglia. Additionally, the degree to which mice are suitable models for human retinal microglia is still not clear. The present study applies fluorescence-activated cell sorting to isolate human retinal microglia from enucleated eyes and compares their transcriptional profile with that of whole retinal tissue, as well as classical, intermediate and non-classical monocytes. In addition, human retinal microglia are compared to murine retinal microglia, isolated from at least two-years old Cx3cr1GFP/+ mice, as well as human brain microglia obtained from the literature. Several overexpressed genes were identified in retinal microglia when compared to whole retinal tissue, as well as classical, intermediate, and non-classical monocytes, among them IL1B, C2, C3, TREM2, P2RY12 and SPP1. In relation to whole retina sequencing, several risk genes, such as APOE and TGBR1, as well as PLXDC2 and ARHGAP22 associated with age-related macular degeneration (AMD) and diabetic retinopathy (DRP), were preferentially expressed in retinal microglia, indicating their potential pathophysiological involvement. The top expressed genes exhibited a strong consistency between retinal and brain microglia, among them CD74, SPP1, ACTB, FTL and C3. There was a high degree of similarity between human and murine retinal microglia, although there were several species-specific genes, revealing for which genes mice are suitable models for human retinal microglia. This study provides detailed insights into the molecular profile of human retinal microglia and indicate a high similarity to brain microglia. It advances our under-standing about their role in human retinal disease, such as AMD and DRP. The similarities and differences between human and mice will facilitate the transferability of knowledge between both species.

Dataset Information

An environment-dependent transcriptional network specifies human microglia identity.

Publications

An environment-dependent transcriptional network specifies human microglia identity.

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