Microglial plasticity governed by state-specific enhancer landscapes.

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Microglia exhibit diverse subpopulations across development, aging, and disease, but their origins and regulatory mechanisms remain unclear.
• The role of enhancer landscapes in microglial identity is known, yet the impact of histone modifications and DNA methylation on microglial state transitions is undefined.

Purpose of the Study:

• To investigate the ontogeny of distinct microglial subpopulations.
• To elucidate the epigenetic regulation of microglial state plasticity.

Main Methods:

• Utilized genetic fate mapping to trace microglial origins and transitions.
• Analyzed transcriptomic and epigenomic profiles of microglial states.

Main Results:

• Demonstrated a common embryonic origin for proliferative-region-associated microglia (PAM).
• Tracked dynamic transitions of PAM into disease-associated microglia (DAM) and white matter-associated microglia (WAM) states.
• Identified state-specific histone modification profiles governing microglial state switches.

Conclusions:

• Microglial states are linked through transcriptomic and epigenomic plasticity, originating from a common lineage.
• Epigenetic modifications, particularly histone modifications at enhancers, are critical regulators of microglial state transitions in health and disease.