Integrative Multiomics Profiling of Mouse Hippocampus Reveals Transcriptional Upregulation of Interferon‐Stimulated Genes Through PU.1 Regulator in Microglial Activation Induced by Chronic Cerebral Hypoperfusion

Chronic cerebral hypoperfusion (CCH) is a significant factor that accelerates cognitive deterioration, yet the mechanisms of hippocampal microglial activation in this context remain unclear. Using an integrative multiomics approach, we investigated the transcriptional and epigenomic landscape of microglial activation in a mouse model of CCH induced by bilateral common carotid artery stenosis. Behavioral assessments revealed cognitive impairments, while neuropathological analysis confirmed hippocampal damage. Proteomic and transcriptomic profiling uncovered significant upregulation of stress and inflammatory pathways, particularly the interferon (IFN) signaling cascade. Epigenomic analysis identified regions of open chromatin, suggesting active transcriptional regulation driven by the transcription factor (TF) PU.1. ChIP-nexus analysis further confirmed that PU.1 directly modulates the expression of IFN-stimulated genes (ISGs), which are pivotal in regulating microglial activation. Our findings demonstrate that PU.1 serves as a key regulator of the IFN-driven microglial response during CCH, mediated by enhanced chromatin accessibility and transcriptional activation of ISGs. This study highlights the critical role of PU.1 in microglial-mediated neuroinflammation and offers potential therapeutic targets for mitigating hippocampal damage associated with chronic cerebral ischemia.