RXR-Mediated Remodeling of Transcriptional and Chromatin Landscapes in APP Mouse Brain: Insights from Integrated Single-Cell RNA and ATAC Profiling
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE283906 | GEO | 2025/12/11
REPOSITORIES: GEO
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| GSE283906_RAW.tar | Raw | |||
| filelist.txt | Txt |
Items per page: 5 1 - 3 of 3 |
Similar Datasets
Project description:Ligand activation of nuclear receptor has been linked with therapeutic implications in Alzheimer's Disease. In this study, we used AD mouse model treated with Bexarotene, an RXR agonist and performed scRNA-seq and snATAC-seq using the brain tissue. We reavealed changes in chromatin architure in brain of AD-lie mouse model in response to RXR ligand and link those changes to the initiation of transcriptional programs at a single-cell resolution.
2025-12-11 | GSE289039 | GEO
Project description:The liver X receptors (LXRs) are nuclear receptors that form permissive heterodimers with retinoid X receptor (RXR) and are important regulators of lipid metabolism in the liver. We have recently shown that RXR agonist-induced hypertriglyceridemia and hepatic steatosis in mice is dependent on LXR and correlates with an LXR-dependent hepatic induction of lipogenic genes. To further investigate the role of RXR and LXR in the regulation of hepatic gene expression, we have mapped the ligand-regulated genome-wide binding of these factors in mouse liver. We find that the RXR agonist bexarotene primarily increases the genomic binding of RXR, whereas the LXR agonist T0901317 greatly increases both LXR and RXR binding. Functional annotation of putative direct LXR target genes revealed a significant association with classical LXR-regulated pathways as well as PPAR signaling pathways, and subsequent ChIP-seq mapping of PPARM-NM-1 binding demonstrated binding of PPARM-NM-1 to 71-88% of the identified LXR:RXR binding sites. Sequence analysis of shared binding regions combined with sequential ChIP on selected sites indicate that LXR:RXR and PPARM-NM-1:RXR bind to degenerate response elements in a mutually exclusive manner. Together our findings suggest extensive and unexpected cross-talk between hepatic LXR and PPARM-NM-1 at the level of binding to shared genomic sites LXR, RXR, PPARalpha and RNA Polymerase II ChIP-seq on livers from female C57BL/6 wild-type and/or LXRM-NM-1/M-NM-2-deficient mice (13 weeks of age, n=1) treated by oral gavage once daily for 14 days with the RXR agonist bexarotene (100 mg/kg body weight [mpk], in 1% carboxymethylcellulose), the LXR agonist T0901317 (T09, 30 mpk) or vehicle alone.
2012-01-31 | E-GEOD-35262 | biostudies-arrayexpress
Project description:RXR agonists, which activate the RXR nuclear receptor, are effective in multiple preclinical cancer models for both treatment and prevention. While RXR is the target of these compounds, the downstream effects on gene expression differs between compounds. To elucidate the effects of the novel RXR agonist MSU 42011 on the transcriptome in tumors of MMTV-Neu mice, we performed RNA sequencing. For comparative analysis, RNA sequencing was also performed on tumors treated with the FDA approved RXR agonist bexarotene. Female MMTV-Neu mice with established mammary tumors 4 mm in diameter were fed control diet, bexarotene (100 mg/kg in diet), or MSU 42011 (100 mg/kg in diet) for 10 days. Both treatments differentially regulated cancer-relevant gene sets, such as focal adhesion, extracellular matrix, and immune pathways. Many of the top genes differentially regulated by RXR agonists are positively associated with survival in breast cancer patients. While MSU 42011 and bexarotene act on many common pathways, these experiments coupled with gene expression analysis of tumors treated with another novel RXR agonist V-125 highlight the differences in regulation of gene expression between these compounds of the same class. Exploration of these unique effects on gene transcription may lead to an increased understanding of the complex biology behind RXR agonists, and how the activities of this diverse class of compounds can be utilized to treat cancer.
2023-02-21 | GSE211290 | GEO
Project description:The liver X receptors (LXRs) are nuclear receptors that form permissive heterodimers with retinoid X receptor (RXR) and are important regulators of lipid metabolism in the liver. We have recently shown that RXR agonist-induced hypertriglyceridemia and hepatic steatosis in mice is dependent on LXR and correlates with an LXR-dependent hepatic induction of lipogenic genes. To further investigate the role of RXR and LXR in the regulation of hepatic gene expression, we have mapped the ligand-regulated genome-wide binding of these factors in mouse liver. We find that the RXR agonist bexarotene primarily increases the genomic binding of RXR, whereas the LXR agonist T0901317 greatly increases both LXR and RXR binding. Functional annotation of putative direct LXR target genes revealed a significant association with classical LXR-regulated pathways as well as PPAR signaling pathways, and subsequent ChIP-seq mapping of PPARα binding demonstrated binding of PPARα to 71-88% of the identified LXR:RXR binding sites. Sequence analysis of shared binding regions combined with sequential ChIP on selected sites indicate that LXR:RXR and PPARα:RXR bind to degenerate response elements in a mutually exclusive manner. Together our findings suggest extensive and unexpected cross-talk between hepatic LXR and PPARα at the level of binding to shared genomic sites
2012-01-31 | GSE35262 | GEO
Project description:The efficiency of central nervous system (CNS) remyelination declines with age. This is in part due to an age-associated decline in the phagocytic removal of myelin debris, which contains inhibitors of oligodendrocyte progenitor cell differentiation. In this study we show that expression of genes involved in the retinoid X receptor (RXR) pathway are decreased with aging in myelin-phagocytosing cells. Loss of RXR function in young macrophages mimics aging by delaying remyelination after experimentally-induced demyelination, while RXR agonists partially restore myelin debris phagocytosis in aged macrophages. The FDA-approved RXR agonist bexarotene, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profile in aging human monocytes to a more youthful profile. These results reveal the RXR pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics. 24 Human CD14+ monocyte-sorted PBMC samples representing 4 Healthy Volunteers (HV) and 4 Multiple Sclerosis (MS) patients under 3 different treatment conditions. Condition 1 = (-) Phagocystosis (-) Bexarotene. Condition 2 = (+) Phagocystosis (-) Bexarotene. Condition 3 = (+) Phagocystosis (+) Bexarotene.
2015-11-04 | E-GEOD-66988 | biostudies-arrayexpress
Project description:To understand the manner by which RAR and RXR program cell state transitions, we performed ChIP-seq to identify their compendium of target genes in an unbiased manner. We exposed the mesenchymal NAMEC8 and SUM159 cancer cells to retinoid treatment, followed by the genome-wide analyses of target gene binding sites for RXR, RAR, H3K27ac and p300. Exposure to bexarotene, a RXR ligand, led to a subset of genes that became bound by RXR, as well as RAR, since both could form heterodimers. These genes furthermore showed increases in p300 binding, and H3K27ac (histone 3, lysine 27 acetylation) modification, which marks gene enhancers.
2021-10-19 | GSE119824 | GEO
Project description:Retinoid X receptor (RXR) is a crucial and distinctive member of the nuclear receptor superfamily, which is involved in regulating various physiological processes. RXR agonists have the potential to treat Alzheimer’s disease (AD). In this study, we identified a novel RXR agonist superior to existing drugs after extensively exploring the biological properties of 6-hydroxy-3’-propyl-[1,1’-biphenyl]-3-propanoic acid (6OHA), a compound synthesized in our laboratory based on the structure of magnaldehyde B. 6OHA exhibited higher selectivity for RXRα over retinoic acid receptor (RARα) and lower transcriptional activity for RXRg compared to the existing RXR agonist bexarotene (Bex). RNA-sequencing analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analyses suggest that 6OHA and Bex exhibit similar gene expression patterns but have distinct transcriptional effects; 6OHA was more closely associated with chemotaxis and response to stimuli compared to Bex. Pharmacokinetic studies revealed that 6OHA exhibited faster intestinal absorption, reached higher concentrations in the brain and liver shortly after oral dministration, and was cleared from the body more rapidly than Bex, subsequently inducing target gene transcription in the brain. Bex increased serum triglyceride and decreased serum thyrotropin and free thyroxine levels, whereas 6OHA did not induce these adverse effects, attributable to the distinct properties of 6OHA as an RXR agonist compared to Bex. Our results highlight 6OHA as a promising RXR agonist for treating AD without any adverse effects.
2024-11-09 | GSE280976 | GEO
Project description:Retinoid X receptor (RXR) is a crucial and distinctive member of the nuclear receptor superfamily, which is involved in regulating various physiological processes. RXR agonists have the potential to treat Alzheimer’s disease (AD). In this study, we identified a novel RXR agonist superior to existing drugs after extensively exploring the biological properties of 6-hydroxy-3’-propyl-[1,1’-biphenyl]-3-propanoic acid (6OHA), a compound synthesized in our laboratory based on the structure of magnaldehyde B. 6OHA exhibited higher selectivity for RXRα over retinoic acid receptor (RARα) and lower transcriptional activity for RXRg compared to the existing RXR agonist bexarotene (Bex). RNA-sequencing analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analyses suggest that 6OHA and Bex exhibit similar gene expression patterns but have distinct transcriptional effects; 6OHA was more closely associated with chemotaxis and response to stimuli compared to Bex. Pharmacokinetic studies revealed that 6OHA exhibited faster intestinal absorption, reached higher concentrations in the brain and liver shortly after oral dministration, and was cleared from the body more rapidly than Bex, subsequently inducing target gene transcription in the brain. Bex increased serum triglyceride and decreased serum thyrotropin and free thyroxine levels, whereas 6OHA did not induce these adverse effects, attributable to the distinct properties of 6OHA as an RXR agonist compared to Bex. Our results highlight 6OHA as a promising RXR agonist for treating AD without any adverse effects.
2025-01-07 | GSE285893 | GEO
Project description:We provide evidence of coordination between heterodimeric nuclear hormone receptor ligands at the genome scale to reveal three unique transcriptional outcomes. First, when stimulated in pancreatic acinar cells, distinct doubly-liganded complexes of the retinoic acid receptor-α (RARα) and retinoid-X-receptor (RXR) bind divergent DNA hormone response elements (HRE). Furthermore, the link between ligand pairs and HRE specificity is correlated with RNA transcript formation. Second, RXR ligands can function as either silent partners or as cooperative effectors on distinct HREs, also with correlated transcriptional outcomes. Third, the absence of unique binding sites on DNA by unliganded RARα:RXR suggests that productive HRE recognition and binding is an exclusive feature of the agonist-bound heterodimer. To achieve the above, DNA-bound heterodimers of RARα:RXR were isolated separately with an RARα-specific antibody, RARα-specific and RXR-specific agonists and the pan-ligand, 9-cis retinoic acid, using the CUT&RUN technique. At each liganded state, transcriptional activity was detected by mRNA sequencing.
2025-02-24 | GSE290329 | GEO
Project description:We provide evidence of coordination between heterodimeric nuclear hormone receptor ligands at the genome scale to reveal three unique transcriptional outcomes. First, when stimulated in pancreatic acinar cells, distinct doubly-liganded complexes of the retinoic acid receptor-α (RARα) and retinoid-X-receptor (RXR) bind divergent DNA hormone response elements (HRE). Furthermore, the link between ligand pairs and HRE specificity is correlated with RNA transcript formation. Second, RXR ligands can function as either silent partners or as cooperative effectors on distinct HREs, also with correlated transcriptional outcomes. Third, the absence of unique binding sites on DNA by unliganded RARα:RXR suggests that productive HRE recognition and binding is an exclusive feature of the agonist-bound heterodimer. To achieve the above, DNA-bound heterodimers of RARα:RXR were isolated separately with an RARα-specific antibody, RARα-specific and RXR-specific agonists and the pan-ligand, 9-cis retinoic acid, using the CUT&RUN technique. At each liganded state, transcriptional activity was detected by mRNA sequencing.
2025-02-24 | GSE290328 | GEO