Cistrome profiles of Retinoids x Receptor alpha (RXRα) , Retinoic Acid Receptor alpha (RARα), and Retinoic Acid Receptor beta (RARβ) in livers of mice treated by control and retionic acid-containing diet
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE53736 | GEO | 2014/01/23
SECONDARY ACCESSION(S): PRJNA232748
REPOSITORIES: GEO
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Project description:Comparison between ChIP-Seq data of RAR? and RAR?, between RAR and RXR, as well as between control and retinoic acid-treatment for each investigated nuclear receptors. Mouse were treated by control diet and RA-diet for 1 days. After treatment, livers were used to do ChIP using antibodies of RXR?, RAR?, and RAR?. An aliquote of total chromatin without pull-down process by any antibodies was used as input control. A single-end read of 35bp sequencing was performed on each of ChIPed DNA and input. Sequencing data of RAR? and RAR? were compared to each other. In addtional, each of RAR? and RAR? data were compared with RXR? data. For each nuclear receptor, ChIP-Seq data prior or after RA-treatment were also compared with each other.
2014-01-23 | E-GEOD-53736 | biostudies-arrayexpress
Project description:Transcriptome analysis of nucleus accumbens shell samples from RARβ-null mutant mice and their wild type littermates The active vitamin A derivative retinoic acid (RA) is an important regulator of adult brain functions. How these regulations are achieved is poorly known, partly due to the paucity of information on RA molecular targets. The striatum, the region involved in control of motor, cognitive and affective functions, may be particularly prone to such regulation as it displays the highest levels of RA and its receptors (RARs). We report the first genome-wide analysis of RAR-binding sites in the brain. Using chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), as well as transcriptomic analysis of RARβ-null mutant mice, we identified genomic transcriptional targets of RARβ in the striatum. Our data point to a strong contribution of RARβ in controlling neurotransmission, energy metabolism, and transcription, with a particular involvement of G-protein, cAMP and calcium signaling. Quantitative PCR analysis of striatal subregions revealed a higher sensitivity of ventral structures (nucleus accumbens) to lack of RARβ signaling. There is a high overlap of transcriptional targets of RARβ and genes affected in expression in Huntington’s disease (HD), and we observed a decrease of RARβ expression in the striatum of R6/2 transgenic mice, a murine model of HD. A large number of genes bearing RARβ binding sites have also been implicated in Alzheimer’s and Parkinson’s diseases, raising the possibility that compromised RA signaling in striatum may be a mechanistic link explaining the similar affective and cognitive symptoms of these diseases. Globally, our data point to a possibility of a neuroprotective function of RARβ in the striatum.
2016-07-26 | GSE67761 | GEO
Project description:The active vitamin A derivative retinoic acid (RA) is an important regulator of adult brain functions. How these regulations are achieved is poorly known, partly due to the paucity of information on RA molecular targets. The striatum, the region involved in control of motor, cognitive and affective functions, may be particularly prone to such regulation as it displays the highest levels of RA and its receptors (RARs). We report the first genome-wide analysis of RAR-binding sites in the brain. Using chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), as well as transcriptomic analysis of RARβ-null mutant mice, we identified genomic transcriptional targets of RARβ in the striatum. Our data point to a strong contribution of RARβ in controlling neurotransmission, energy metabolism, and transcription, with a particular involvement of G-protein, cAMP and calcium signaling. Quantitative PCR analysis of striatal subregions revealed a higher sensitivity of ventral structures (nucleus accumbens) to lack of RARβ signaling. There is a high overlap of transcriptional targets of RARβ and genes affected in expression in Huntington’s disease (HD), and we observed a decrease of RARβ expression in the striatum of R6/2 transgenic mice, a murine model of HD. A large number of genes bearing RARβ binding sites have also been implicated in Alzheimer’s and Parkinson’s diseases, raising the possibility that compromised RA signaling in striatum may be a mechanistic link explaining the similar affective and cognitive symptoms of these diseases. Globally, our data point to a possibility of a neuroprotective function of RARβ in the striatum.
2016-07-22 | GSE67829 | GEO
Project description:All-trans-retinoic acid (RA), a potent inducer of cellular differentiation, functions as a ligand for retinoic acid receptors (RARα, β, and γ). RARs are activated by ligand binding, which induces transcription of direct genomic targets. However, whether embryonic stem cells respond to RA through routes that do not involve RARs is unknown. Here, we used CRISPR technology to introduce biallelic frameshift mutations in RARα, RARβ, and RARγ, thereby abrogating all RAR functions in murine embryonic stem cells. We then evaluated RA-responsiveness of the RAR-null cells using RNA-Seq transcriptome analysis. We found that the RAR-null cells display no changes in transcripts in response to RA, demonstrating that the RARs are essential for the regulation of all transcripts in murine embryonic stem cells in response to RA. Our key finding, that in embryonic stem cells the transcriptional effects of RA all depend on RARs, addresses a long-standing topic of discussion in the field of retinoic acid signaling.
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Project description:Various studies have suggested a link between vitamin A (VA), all-trans-retinol, and type 2 diabetes (T2D). However, the functional role/expression of vitamin A receptors (Rarα, β, and γ) in pancreatic β-cells is not clear yet. Accordingly, we performed a series of bioinformatics, molecular and functional experiments in human islet and INS-1 cells to evaluate the role of Rarβ on insulin secretion and pancreatic β-cell function. Microarray and RNA-sequencing (RAN-seq) expression analysis showed that RARα, β, and γ are expressed in human pancreatic islets. RNA-seq expression of RARβ in diabetic/hyperglycemic human islets (HbA1c ≥ 6.3%) revealed a significant reduction (p = 0.004) compared to nondiabetic/normoglycemic cells (HbA1c < 6%). The expression of RARβ with INS and PDX1 showed inverse association, while positive correlations were observed with INSR and HbA1c levels. Exploration of the T2D knowledge portal (T2DKP) revealed that several genetic variants in RARβ are associated with BMI. The most associated variant is rs6804842 (p = 1.2 × 10−25). Silencing of Rarβ in INS-1 cells impaired insulin secretion without affecting cell viability or apoptosis. Interestingly, reactive oxygen species (ROS) production levels were elevated and glucose uptake was reduced in Rarβ-silenced cells. mRNA expression of Ins1, Pdx1, NeuroD1, Mafa, Snap25, Vamp2, and Gck were significantly (p < 0.05) downregulated in Rarβ-silenced cells. For protein levels, Pro/Insulin, PDX1, GLUT2, GCK, pAKT/AKT, and INSR expression were downregulated considerably (p < 0.05). The expression of NEUROD and VAMP2 were not affected. In conclusion, our results indicate that Rarβ is an important molecule for β-cell function. Hence, our data further support the potential role of VA receptors in the development of T2D.
| S-EPMC9312298 | biostudies-literature
Project description:Human pluripotent stem cell (hPSC)-derived cardiomyocytes have proven valuable for modeling disease and as a drug screening platform. Here, we depict an optimized protocol for the directed differentiation of hPSCs toward cardiomyocytes with an atrial identity by modulating the retinoic acid signaling cascade in spin embryoid bodies. The crucial steps of the protocol, including hPSC maintenance, embryoid body (EB) differentiation, the induction of cardiac mesoderm, direction toward the atrial phenotype, as well as molecular and functional characterization of the cardiomyocytes, are described. Atrial cardiomyocytes (AMs) can be generated within 14 days. Most importantly, we show that induction of the specific retinoic acid receptor alpha (RARα) increased the efficiency of atrial differentiation to 72% compared with 45% after modulating the retinoic acid (RA) pathway with all-trans RA (atRA). In contrast, the induction of RARβ signaling only had a minor impact on the efficiency of atrial differentiation (from about 45% to 50%). Similarly, the total yield of AM per EB of 5000 hPSCs was increased from 10,350 (2.07 per hPSC) to 16,120 (3.22 per hPSC) while selectively modulating RARα signaling. For further purification of the AMs, we describe a metabolic selection procedure that enhanced the AM percentage to more than 90% without compromising the AM yield (15,542 per EB, equal to 3.11 per hPSC) or functionality of the AMs as evaluated by RNAseq, immunostaining, and optical action potential measurement. Cardiomyocytes with distinct atrial and ventricular properties can be applied for selective pharmacology, such as the development of novel atrial-specific anti-arrhythmic agents, and disease modeling, including atrial fibrillation, which is the most common heart rhythm disorder. Moreover, fully characterized and defined cardiac subtype populations are of the utmost importance for potential cell-based therapeutic approaches.
| S-EPMC9032956 | biostudies-literature
Project description:Background & Aims: Alcohol-associated liver disease (ALD) is associated with loss of vitamin A (retinoids), increased steatosis, and greater oxidative stress. Although a strong correlation has been observed between loss of retinoids and ALD, if retinoid loss plays a causal role in the pathophysiology of ALD is not clear. Approach & Results: Based on our prior published data indicating that a selective retinoic acid receptor beta (RARβ) agonist limits nonalcohol-related liver disease (NAFLD) pathology, we generated AlbCre;RARβ knockout (BKO) mice and fed these mice a Lieber DeCarli ethanol diet (ETOH). We also generated cultured human hepatocytes (HepG2) that lack RARβ (RARβ-KO) and treated them with ETOH. Here we show that the livers of BKO mice develop greater steatosis, oxidative stress (assessed by 4-HNE), cell proliferation, and hypertrophy on the ETOH diet when compared to wild type (WT). Compared to ETOH-WT mice, the ETOH-BKO mice also exhibit higher hepatic transcript levels of ATF4, MYC, a subset of integrated stress response (ISR) genes (Trib3, Asns, Nqo1, and Hmox1), and the common ATF4 and MYC target, 4EBP1(EIF4EBP1). In RARβ-KO HepG2 cells, ETOH treatments (24 and 72h) resulted in more rapid and greater development of reactive oxygen species compared to parental HepG2. Notably, even without ETOH, ATF4 protein was higher in the RARβ-KO than in parental HepG2. Conclusions: Our research identifies hepatocyte RARβ as a crucial negative regulator of oxidative stress, MYC, ATF4, and proliferation in ALD.
2023-11-28 | GSE221713 | GEO
Project description:Retinoic acid (RA)-elicited signaling has been shown to play critical roles in development, organogenesis, and the immune response. RA regulates expression of Alzheimer's disease (AD)-related genes and attenuates amyloid pathology in a transgenic mouse model. In this study, we investigated whether RA can suppress the production of amyloid-β (Aβ) through direct inhibition of γ-secretase activity. We report that RA treatment of cells results in significant inhibition of γ-secretase-mediated processing of the amyloid precursor protein C-terminal fragment APP-C99, compared with DMSO-treated controls. RA-elicited signaling was found to significantly increase accumulation of APP-C99 and decrease production of secreted Aβ40. In addition, RA-induced inhibition of γ-secretase activity was found to be mediated through significant activation of extracellular signal-regulated kinases (ERK1/2). Treatment of cells with the specific ERK inhibitor PD98059 completely abolished RA-mediated inhibition of γ-secretase. Consistent with these findings, RA was observed to inhibit secretase-mediated proteolysis of full-length APP. Finally, we have established that RA inhibits γ-secretase through nuclear retinoic acid receptor-α (RARα) and retinoid X receptor-α (RXRα). Our findings provide a new mechanistic explanation for the neuroprotective role of RA in AD pathology and add to the previous data showing the importance of RA signaling as a target for AD therapy.
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Project description:Genome-wide binding of Retinoids x Receptor and Retinoic Acid Receptor in mouse liver was described
2013-05-15 | GSE46762 | GEO
Project description:Nuclear receptors (NRs) activate transcription of target genes in response to binding of ligands to their ligand-binding domains (LBDs). Typically, in vitro assays use either gene expression or the recruitment of coactivators to the isolated LBD of the NR of interest to measure NR activation. However, this approach ignores that NRs function as homo- as well as heterodimers and that the LBD harbors the main dimerization interface. Cofactor recruitment is thereby interconnected with oligomerization status as well as ligand occupation of the partnering LBD through allosteric cross talk. Here we present a modular set of homogeneous time-resolved FRET-based assays through which we investigated the activation of PPARγ in response to ligands and the formation of heterodimers with its obligatory partner RXRα. We introduced mutations into the RXRα LBD that prevent coactivator binding but do not interfere with LBD dimerization or ligand binding. This enabled us to specifically detect PPARγ coactivator recruitment to PPARγ:RXRα heterodimers. We found that the RXRα agonist SR11237 destabilized the RXRα homodimer but promoted formation of the PPARγ:RXRα heterodimer, while being inactive on PPARγ itself. Of interest, incorporation of PPARγ into the heterodimer resulted in a substantial gain in affinity for coactivator CBP-1, even in the absence of ligands. Consequently, SR11237 indirectly promoted coactivator binding to PPARγ by shifting the oligomerization preference of RXRα toward PPARγ:RXRα heterodimer formation. These results emphasize that investigation of ligand-dependent NR activation should take NR dimerization into account. We envision these assays as the necessary assay tool kit for investigating NRs that partner with RXRα.
| S-EPMC8258697 | biostudies-literature