A Study of Allostery Within Liganded RARα:RXR Heterodimers at the Genome Scale [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1227494 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32467485_1.fastq.gz | Fastqsanger.gz | |||
| SRR32467485_2.fastq.gz | Fastqsanger.gz | |||
| SRR32467486_1.fastq.gz | Fastqsanger.gz | |||
| SRR32467486_2.fastq.gz | Fastqsanger.gz | |||
| SRR32467487_1.fastq.gz | Fastqsanger.gz |
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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
Project description:A Study of Allostery Within Liganded RARα:RXR Heterodimers at the Genome Scale [CUT&Run]
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Project description:We defined the RARα interactome in the MDA-MB453 breast cancer cell line genetically engineered to over-express an N-terminally tagged version of the nuclear retinoic acid receptor. Twenty eight nuclear proteins which interact with RARα and whose interaction is stimulated or reduced by the pan-RAR ligand, all-trans retinoic acid (ATRA) were identified. Given the potential significance of the S100A3 calcium-binding protein in the control of tumor progression, we focused our attention on this factor. Using the two models represented by the ATRA-sensitive SKBR3 and MCF7 breast cancer cell lines characterized by constitutive expression of S100A3 and RARα, we demonstrate that the endogenous forms of S100A3 and RARα interact in physiological conditions. The interaction of S100A3 with RARα is cell context independent and it is observed not only in breast cancer but also in acute promyelocytioc leukemia (APL) cells, characterized by expression of the RARα-derived PML-RARα oncogene, which is the product of the t(15:17) chromosomal translocation. S100A3 interacts directly and specifically with RARα and PML-RARα, being unable to bind other members of the RAR/RXR family of retinoid nuclear receptors. The interaction surface maps to the carboxyl-terminal region of the RARα ligand binding domain. Binding of S100A3 to RARα and PML-RARα controls the constitutive and ATRA-dependent degradation of the two receptors. Silencing of the S100A3 gene decreases the amounts of RARα in breast SK-BR-3 and lung A549 cancer cells, rendering them more refractory to the anti-proliferative action of ATRA. In SK-BR-3 cells, this effect is accompanied by a decrease in the lactogenic/differentiating action of ATRA. In APL-derived NB4 cells, S100A3 knock-down reduces the amounts of both RARα and PML-RARα. Contemporaneous down-regulation of the two receptors is associated with an increase in the basal and ATRA-induced expression of many granulocytic differentiation markers. Opposite on RARα and PML-RARα levels as well as ATRA induced differentiation markers are observed upon over-expression of S100A3 in NB4 cells.
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Project description:Thyroid hormones such as 3,3',5 triiodo-L-thyronine (T3) control numerous aspects of mammalian development and metabolism. The actions of such hormones are mediated by specific thyroid hormone receptors (TRs). TR belongs to the nuclear receptor family of modular transcription factors that binds to specific DNA-response elements within target promoters. These receptors can function as homo- or heterodimers such as TR:9-cis retinoic acid receptor (RXR). Here, we present the atomic resolution structure of the TRα•T3:RXRα•9-cis retinoic acid (9c) ligand binding domain heterodimer complex at 2.95 Å along with T3 hormone binding and dissociation and coactivator binding studies. Our data provide a structural basis for allosteric communication between T3 and 9c and negative cooperativity between their binding pockets. In this structure, both TR and RXR are in the active state conformation for optimal binding to coactivator proteins. However, the structure of TR•T3 within TR•T3:RXR•9c is in a relative state of disorder, and the observed kinetics of binding show that T3 dissociates more rapidly from TR•T3:RXR•9c than from TR•T3:RXR. Also, coactivator binding studies with a steroid receptor coactivator-1 (receptor interaction domains 1-3) fragment show lower affinities (K(a)) for TR•T3:RXR•9c than TR•T3:RXR. Our study corroborates previously reported observations from cell-based and binding studies and offers a structural mechanism for the repression of TR•T3:RXR transactivation by RXR agonists. Furthermore, the recent discoveries of multiple endogenous RXR agonists that mediate physiological tasks such as lipid biosynthesis underscore the pharmacological importance of negative cooperativity in ligand binding within TR:RXR heterodimers.
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Project description:Comparison between ChIP-Seq data of RARα and RARβ, between RAR and RXR, as well as between control and retinoic acid-treatment for each investigated nuclear receptors.
2014-01-23 | GSE53736 | GEO
Project description:Retinoic Acid Receptors (RARs) as a functional heterodimer with Retinoid X Receptors (RXRs), bind a diverse series of RA-response elements (RAREs) in regulated genes. Among them, the non-canonical DR0 elements are bound by RXR-RAR with comparable affinities to DR5 elements but DR0 elements do not act transcriptionally as independent RAREs. In this work, we present structural insight for the recognition of DR5 and DR0 elements by RXR-RAR heterodimer using x-ray crystallography, small angle x-ray scattering, and hydrogen/deuterium exchange coupled to mass spectrometry. We solved the crystal structure of RXR-RAR DNA-binding domain in complex with the Rarb2 DR5 and RXR DNA-binding domain in complex with Hoxb13 DR0. While cooperative binding was observed on DR5, on DR0 the two molecules bound non-cooperatively on opposite sides of the DNA. In addition, our data unveil the structural organization and dynamics of the multi-domain RXR-RAR DNA complexes providing evidence for DNA-dependent allosteric communication between domains. Differential binding mode between DR0 and DR5 were observed leading to differences in the conformation and structural dynamics of the multi-domain RXR-RAR DNA complex. These results reveal that the topological organization of the RAR binding element confer regulatory information by modulating the overall topology and structural dynamics of the RXR-RAR heterodimers.
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Project description:Genome-wide profiling of PPARγ:RXR and RNA polymerase II reveals temporal activation of distinct metabolic pathways in RXR dimer composition during adipogenesis. Chromatin immunoprecipitation combined with deep sequencing was performed to generate genome-wide maps of peroxisome prolifelator-activated receptor gamma (PPARg) and retinoid X receptor (RXR) binding sites, and RNA polymerase II (RNAPII) occupancy at high resolution throughout adipocyte differentiation of 3T3-L1 cells. The data provides the first positional and temporal map PPARγ and RXR occupancy during adipocyte differentiation at a global scale. The number of PPARγ:RXR shared binding sites is steadily increasing from D0 to D6. At Day6 there are over 5000 high confidence shared PPARy:RXR binding sites. We show that at the early days of differentiation several of these sites bind not only PPARγ:RXR but also other RXR dimers. The data also provides a comprehensive temporal map of RNAPII occupancy at genes throughout 3T3-L1 adipogenesis thereby uncovering groups of similarly regulated genes belonging to glucose and lipid metabolic pathways. The majority of the upregulated but very few downregulated genes have assigned PPARγ:RXR target sites, thereby underscoring the importance of PPARγ:RXR in gene activation during adipogenesis and indicating that a hitherto unrecognized high number of adipocyte genes are directly activated by PPARγ:RXR
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Project description:Genome-wide profiling of PPAR?:RXR and RNA polymerase II reveals temporal activation of distinct metabolic pathways in RXR dimer composition during adipogenesis. Chromatin immunoprecipitation combined with deep sequencing was performed to generate genome-wide maps of peroxisome prolifelator-activated receptor gamma (PPARg) and retinoid X receptor (RXR) binding sites, and RNA polymerase II (RNAPII) occupancy at high resolution throughout adipocyte differentiation of 3T3-L1 cells. The data provides the first positional and temporal map PPAR? and RXR occupancy during adipocyte differentiation at a global scale. The number of PPAR?:RXR shared binding sites is steadily increasing from D0 to D6. At Day6 there are over 5000 high confidence shared PPARy:RXR binding sites. We show that at the early days of differentiation several of these sites bind not only PPAR?:RXR but also other RXR dimers. The data also provides a comprehensive temporal map of RNAPII occupancy at genes throughout 3T3-L1 adipogenesis thereby uncovering groups of similarly regulated genes belonging to glucose and lipid metabolic pathways. The majority of the upregulated but very few downregulated genes have assigned PPAR?:RXR target sites, thereby underscoring the importance of PPAR?:RXR in gene activation during adipogenesis and indicating that a hitherto unrecognized high number of adipocyte genes are directly activated by PPAR?:RXR Examination of PPARg and RXR bindingsites during adipocyte differentiation (day 0 to 6) and association with transcription via RNAPII occupancy.
2008-12-10 | E-GEOD-13511 | biostudies-arrayexpress