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Updated: Sep 8, 2025
Multiplexed Analysis of Retinal Gene Expression and Chromatin Accessibility Using scRNA-Seq and scATAC-Seq
Published on: March 12, 2021
Decoding the Effects of Bexarotene treatment on brain of AD-like model mice: Single-Cell Transcriptomics and
Yi Lu1, Xuebao Wang1, Carolina Saibro-Girardi1
1University of Pittsburgh.
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.
Insights
Retinoid X Receptor (RXR) activation by Bexarotene modulates gene networks critical for brain health, potentially offering new therapeutic avenues for neurodegenerative diseases by restoring homeostasis.
Area of Science:
- Neuroscience
- Molecular Biology
- Genomics
Background:
- Ligand-activated Retinoid X Receptors (RXRs) are crucial for neural development, neuroinflammation, and metabolism.
- Understanding RXR's influence on chromatin and gene expression is key for treating neurodegenerative diseases.
Purpose of the Study:
- To investigate RXR-mediated regulatory mechanisms in a mouse model of Alzheimer's disease.
- To elucidate the epigenomic and transcriptional effects of RXR activation.
Main Methods:
- Integrated single-nucleus ATAC-seq (snATAC-seq) and single-cell RNA-seq (scRNA-seq).
- Validated chromatin accessibility with RXR ChIP-seq.
- Performed transcription factor (TF) footprinting to map RXR-activated regulatory networks.
Main Results:
- Identified a multilayered transcriptional cascade initiated by RXR signaling.
- Revealed RXR-centered circuits involving TF heterodimer activation and metabolic pathway induction.
- Bexarotene modulates existing TF networks rather than dismantling neuronal regulatory scaffolds.
Conclusions:
- Integrated omics approaches provide comprehensive analysis of RXR transcriptional regulation.
- RXR activation orchestrates gene networks to restore brain homeostasis in disease contexts.
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