Decoding the Effects of Bexarotene treatment on brain of AD-like model mice: Single-Cell Transcriptomics and Chromatin Accessibility Analysis.

Backgound: Ligand-activated Retinoid X Receptors (RXRs) regulate gene networks essential for neural development, neuroinflammation, and metabolism. Understanding how RXR activation influences chromatin architecture and gene expression may reveal therapeutic strategies for neurodegenerative diseases. Methods: We used Bexarotene-treated APP/PS1ΔE9 mice to study RXR-mediated regulatory mechanisms. To investigate epigenomic and transcriptional effects, we integrated single-nucleus ATAC-seq (snATAC-seq) with single-cell RNA-seq (scRNA-seq) and validated differentially accessible chromatin peaks using RXR ChIP-seq. Transcription factor (TF) footprinting analysis were performed to map regulatory networks activated by ligand-bound RXR. Results: Our integrated analyses revealed a multilayered transcriptional cascade initiated by a single linear RXR signaling event. We identified RXR-centered regulatory circuits involving heterodimer activation, subsequent upregulation of multiple downstream TFs, and induction of metabolic pathways relevant to neural function. The results of a detailed analysis of TF regulatory networks in neuronal systems suggests that Bexarotene doesn't dismantle the fundamental regulatory scaffold in neurons but rather modulates RXR regulatory role through existing TF networks. Conclusions: This study demonstrates that combining scRNA-seq, snATAC-seq, and ChIP-seq enables a comprehensive analysis of RXR-mediated transcriptional regulation. RXR activation orchestrates complex gene networks that may help restore brain homeostasis in the context of amyloid pathology, neuroinflammation, and neuronal injury.