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Transcriptomic changes in human SCC-25 Parental and RARG knockout cells in response to 6h and 48h treatments with RARγ agonists CD1530 or all-trans retinoic acid (RA).

ABSTRACT: Vitamin A (retinol) metabolism and signaling through nuclear retinoic acid receptors (RARs α,β,γ) regulate embryonic development, immune functions, and cell differentiation in most cell types. RAR gamma (RARγ) is highly expressed in stratified squamous epithelial cells of the tongue, esophagus, and skin. While data indicate that RARγ agonism is anti-tumorigenic in oral cavity squamous cell carcinoma (OCSCC), the specific, primary gene targets of RARγ remain poorly characterized. Here, we define the transcriptomic consequences of RARγ activity in OCSCC. Using a CRISPR-Cas9-mediated knockout (KO) of RARγ and pharmacological treatments with RAR agonists, we identified RARγ-specific gene targets and pathways, as well as targets that overlap with other RA-responsive nuclear receptors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295225 | GEO | 2025/12/12

REPOSITORIES: GEO

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CUT&RUN in SCC-25 Parental and RARG knockout cells maps RARγ binding sites and genome wide changes in H3K4 & H3K27 trimethylation

Project description:Vitamin A (retinol) metabolism and signaling through nuclear retinoic acid receptors (RARs α,β,γ) regulate embryonic development, immune functions, and cell differentiation in most cell types. RAR gamma (RARγ) is highly expressed in stratified squamous epithelial cells of the tongue, esophagus, and skin. While data indicate that RARγ agonism is anti-tumorigenic in oral cavity squamous cell carcinoma (OCSCC), the specific, primary gene targets of RARγ remain poorly characterized. Here, we define the transcriptomic consequences of RARγ activity in OCSCC. Using a CRISPR-Cas9-mediated knockout (KO) of RARγ and pharmacological treatments with RAR agonists, we identified RARγ-specific gene targets and pathways, as well as targets that overlap with other RA-responsive nuclear receptors.

2025-12-12 | GSE295226 | GEO

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Project description:How cells respond to different external cues to develop along defined cell lineages composing complex tissues is a major question in systems biology. In this study, we studied the role of synthetic agonists targeting specific Retinoic acid receptors (RARs) on activating major gene regulatory wires driving cell specialization during nervous tissue formation issued from P19 stem cells. Specifically, we have revealed that the synergistic activation of the RAR and RAR nuclear receptors by their cognate ligands (BMS641 or BMS961) induce neuronal maturation, inlcuding specialized neuronal subtypes as well as to astrocytes and oligodendrocyte precursors. With the help of Rar-null mutant lines, combined with the use of RAR-specific agonists, global transcriptome mapping and an in-silico modeling of transcription regulatory signalling propagation, we have highlighted major gene programs essential for optimal neuronal cell specialization. Overall, this study provides a systems biology view of the gene programs behind the previously observed redundancy between RAR receptors, paving the way for their potential use for directing cell specialization during nervous tissue formation.

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Transcript levels in CCE WT and RARgamma knockout murine embryonic stem cells treated with either all-trans retinoic acid (8 and 24 hr) or with vehicle control

Project description:Retinoic acid receptors (RARs) α, β, and γ heterodimerize with Retinoid X receptors (RXR) α, β, and γ and bind the cis-acting response elements known as RAREs to execute the biological functions of retinoic acid during mammalian development. RARγ mediates the anti-proliferative and apoptotic effects of retinoids in certain tissues and cancer cells, such as melanoma and neuroblastoma cells. Furthermore, ablation of RARγ enhanced the tumor incidence of Ras transformed keratinocytes and was associated with resistance to retinoid mediated growth arrest and apoptosis. We used microarray analysis to identify genes, which upon 8 or 24 hr of treatment with all-trans retinoic acid display differential expression in RARγ knockout (RARγKO) murine embryonic stem cells relative to CCE WT cells. We demonstrate that following RA treatment the majority of inducible transcripts are present at lower levels in RARγKO ES cells compared to WT ES cells.

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Non-clinical and clinical pharmacology of the potent and selective RARγ agonist trifarotene

Project description:Background: First- and third-generation retinoids are the main treatment in acne. Even though efficacious, they lack full selectivity for RARγ expressed in the epidermis and infundibulum. Objectives: To characterize the in vitro metabolism and the pharmacology of the novel retinoid trifarotene. Methods: In vitro assays determined efficacy, potency and selectivity on RARs, as well as the activity on the expression of retinoid target genes in human keratinocytes and ex vivo cultured skin. In vivo studies investigated topical comedolytic, anti-inflammatory and depigmenting properties. The trifarotene-induced gene expression profile was investigated in non-lesional skin of acne patients and compared to ex vivo and in vivo models. Finally, the metabolic stability in human keratinocytes and hepatic microsomes was established. Results: Trifarotene is a selective RARγ agonist with >20-fold selectivity over RAR and RARβ. Trifarotene is active and stable in keratinocytes but rapidly metabolized by human hepatic microsomes, predicting improved safety. In vivo, trifarotene 0.01% applied topically is highly comedolytic and has antiinflammatory and antipigmenting properties. Gene expression studies indicated potent activation of known retinoid-modulated processes (epidermal differentiation, proliferation, stress response, RA metabolism) and novel pathways (proteolysis, transport/skin hydration, cell adhesion) in ex vivo and in vivo models, as well as in human skin after four weeks of topical application of trifarotene 0.005% cream. Conclusion: Based on its RARγ selectivity, rapid degradation in human hepatic microsomes and pharmacological properties including potent modulation of epidermal processes, topical treatment with trifarotene is expected to provide strong efficacy combined with a favourable safety profile in acne and ichthyotic disorders.

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Combinatorial knockout of RARα, RARβ, and RARγ completely abrogates transcriptional responses to retinoic acid in murine embryonic stem cells

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2018-05-25 | GSE112412 | GEO

Relocalization of retinoic acid receptors from non-canonical to canonical spaced binding elements during embryoid body differentiation

Project description:Retinoic Acid Receptors (RARs) bind RA-response elements in regulatory regions of their target genes. While canonical RAREs comprise direct repeats of the consensus 5’-RGKTCA-3’ sequence separated by 1, 2 or 5 nucleotides (DR1, DR2, DR5), we show that shortly after RA treatement of mouse embryoid bodies or F9 cells, RARs occupy a large repertoire of DR0, DR2, DR5, DR8 and IR0 elements. In vitro, RAR-RXR bind these non-canonical spacings with comparable affinities to DR2 and DR5. Most DR8 elements comprise three half sites with DR2 and DR0 spacings. This specific half site organisation constitutes a previously unrecognised, but frequent signature of RAR binding elements and acts as an RARE. At later stages of embryoid body differentiation, RARs relocalise to a restricted repertoire of sites comprising predominantly DR5 elements. Differentiation thus involves genomic relocalisation of RARs, and a switch from DR0 and DR8 at early times to DR5 at later stages. Examination of genomic localisation of RAR in differentiating embryoid bodies.

2012-06-15 | E-GEOD-35599 | biostudies-arrayexpress

Relocalization of retinoic acid receptors from non-canonical to canonical spaced binding elements during embryoid body differentiation

2012-06-15 | GSE35599 | GEO

New structural insights into the control of the retinoic acid receptors RAR/RXR by DNA, ligands and transcriptional coregulators

Project description:Retinoic acid receptors (RARs) are ligand-dependent transcription factors essential for various biological processes, including embryogenesis, differentiation, and apoptosis. RARs function as heterodimers with retinoid X receptors (RXRs) and regulate gene expression via retinoic acid response elements (RAREs). Their transcriptional activity is modulated by coregulators, with corepressors maintaining repression in the absence of ligand and coactivators enabling transcription upon ligand binding. Structural studies reveal that DNA binding induces conformational changes affecting coregulator interactions. However, the precise structural organization of RAR/RXR-coregulator complexes and the allosteric influence of DNA on receptor function remain incompletely understood. Our study presents an integrative analysis of the RAR/RXR heterodimer bound to four distinct RAREs (DR0, DR1, DR5, and IR0) in complex with either a corepressor (NCoR) or a coactivator (TIF-2) nuclear receptor interaction domain. By combining SAXS data and molecular dynamics simulations, the findings reveal that the heterodimer adopts distinct conformations depending on the DNA sequence, influencing interdomain distances and receptor interactions. Additionally, HDX-MS analysis uncovers the dynamic interplay between ligand, DNA, and coregulator binding. Notably, the study provides new insights into the structural features of coregulator proteins and highlights the allosteric influence of RAREs on receptor function.

2025-10-03 | PXD061924 | Pride

Structural basis for DNA recognition and allosteric control of the Retinoic Acid Receptors RAR-RXR

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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