Transcription factors that define the epigenome structures and transcriptomes in microglia.

Microglia, the resident macrophages of the brain, play critical roles in maintaining brain health. Recent genome-wide analyses, including ATAC-seq, ChIP-seq/CUT&RUN, and single-cell RNA-seq, have identified key transcription factors that define the transcriptome programs of microglia. Four transcription factors-PU.1, IRF8, SALL1, and SMAD4-form enhancer complexes and act as lineage-determining factors, shaping microglial identity. These factors co-bind with other lineage-determining transcription factors, directing one toward designated regions that program microglia while inhibiting the other from binding to DNA. Other transcription factors, such as BATF3 and MAFB, contribute to transcriptional cascades in microglia. TGF-β is a crucial cytokine driving these transcription factors to bind DNA and maintain homeostatic microglia. These findings provide insights into the physiological aspects of microglia and their roles in neuroinflammatory and neurodegenerative diseases.