RXR-Mediated Remodeling of Transcriptional and Chromatin Landscapes in APP Mouse Brain: Insights from Integrated Single-Cell RNA and ATAC Profiling.

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 mechanisms relevant to neurodegenerative diseases. We used Bexarotene-treated APP/PS1ΔE9 mice to study RXR-mediated regulatory mechanisms by integrating single-nucleus ATAC-seq (snATAC-seq) with single-cell RNA-seq (scRNA-seq) and validating differentially accessible chromatin peaks using RXR ChIP-seq. Transcription factor (TF) footprinting analysis mapped regulatory networks activated by ligand-bound RXR. Our integrated analyses revealed a multilayered transcriptional cascade initiated by RXR signaling. We identified RXR-centered regulatory circuits involving heterodimer activation, upregulation of downstream TFs, and induction of metabolic pathways relevant to neural function. Detailed analysis of neuronal TF networks revealed that Bexarotene modulates RXR's role through existing regulatory scaffolds rather than creating new ones. This study demonstrates that combining scRNA-seq, snATAC-seq, and ChIP-seq enables comprehensive analysis of RXR-mediated transcriptional regulation. RXR activation orchestrates cell-type-specific chromatin remodeling of gene networks controlling neuroinflammation, lipid metabolism, and synaptic signaling, providing mechanistic insights into RXR-dependent transcriptional programs in Alzheimer's disease pathology.