State-specific enhancer landscapes govern microglial plasticity

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Single-cell transcriptomics reveals diverse microglial states in brain development, aging, and disease.
• The origin and plasticity of these microglial subsets remain unclear.
• The role of epigenetic modifications in regulating microglial state transitions at enhancers is not well-defined.

Purpose of the Study:

• To investigate the ontogeny and plasticity of microglial subpopulations.
• To define the role of histone modifications and DNA methylation in microglial state switching.

Main Methods:

• Genetic fate mapping was employed to trace microglial development.
• Transcriptomic and epigenomic analyses were performed.

Main Results:

• Demonstrated a common embryonic origin for distinct microglial states, including those in developing white matter.
• Tracked dynamic transitions between proliferative-region-associated microglia, disease-associated microglia, and white matter-associated microglia.
• Identified state-specific enhancer histone modifications and transcription regulators governing these transitions.

Conclusions:

• Microglial states are linked by transcriptomic and epigenomic plasticity, originating from a common embryonic source.
• Epigenetic mechanisms, including histone modifications, regulate microglial state transitions.
• This provides insights into microglial roles in health and disease.