Microglia recapitulate a hematopoietic master regulator network in the aging human frontal cortex

Area of Science:

• Neuroimmunology
• Neuroscience
• Aging Research

Background:

• Microglia are the brain's primary immune cells.
• Previous research suggested altered microglial states in aging brains, but data from human brain tissue is limited.

Purpose of the Study:

• To investigate age-dependent changes in microglia gene expression in the adult human frontal cortex.
• To identify master regulators controlling microglial gene expression modules associated with aging.

Main Methods:

• Analysis of three transcriptome datasets from postmortem human frontal cortex samples (n=381).
• Gene coexpression network analysis to identify microglial transcriptional modules.
• Identification and validation of master regulators (MRs) using ChIP-Seq and protein-protein interaction data.

Main Results:

• Microglia gene markers formed a transcriptional module, predominantly M1 and M1/M2b phenotypes.
• Expression of this module declined with age, particularly for surface receptors involved in cell crosstalk.
• A subnetwork of transcription factors (RUNX1, IRF8, PU.1, TAL1) were identified as master regulators of this age-dependent module.

Conclusions:

• Microglial gene expression and activation states change significantly with age in the human brain.
• Specific transcription factors (RUNX1, IRF8, PU.1, TAL1) are crucial for regulating microglial homeostasis in the adult brain.
• These findings highlight the role of microglia regulation in brain aging and development.