Human microglia maturation is underpinned by specific gene regulatory networks

Area of Science:

• Neuroscience
• Developmental Biology
• Immunology

Background:

• Microglia, the brain's immune cells, have diverse phenotypes influenced by their environment.
• The transcriptional networks governing human microglia maturation remain largely unknown.
• Understanding these networks is crucial for deciphering microglia's role in brain health and disease.

Purpose of the Study:

• To characterize the transcriptional and epigenetic landscapes of human microglia across different developmental stages.
• To predict gene regulatory networks (GRNs) involved in microglia maturation.
• To establish models for studying human microglia development and function.

Main Methods:

• Collected transcriptomic and epigenetic data from fetal and postnatal human microglia.
• Utilized induced pluripotent stem cell (iPSC)-derived microglia and cerebral organoids.
• Employed computational approaches to predict transcription factor (TF) co-occurrence and enhancer activity for GRN inference.
• Engrafted iPSC-derived microglia into humanized mice to model developmental transitions.

Main Results:

• Identified stage-specific transcriptomes and epigenetic landscapes of human microglia.
• Predicted shared and state-specific GRNs associated with fetal and postnatal microglia.
• Demonstrated recapitulation of human fetal-to-postnatal microglia transition in humanized mouse models.
• Developed computational tools for analyzing microglia gene regulation.

Conclusions:

• The study provides a comprehensive map of gene regulatory networks governing human microglia maturation.
• The findings offer insights into the mechanisms underlying microglia phenotype acquisition.
• The developed models and data facilitate future research into microglia-specific functions and diseases.