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| Status |
Public on Apr 02, 2024 |
| Title |
The retinoid X receptor has a critical role in synthetic rexinoid-induced increase in cellular all-trans-retinoic acid |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Rexinoids are agonists of nuclear rexinoid X receptors (RXR) that heterodimerize with other nuclear receptors to regulate gene transcription. A number of selective RXR agonists have been developed for clinical use but their application has been hampered by the unwanted side effects associated with the use of rexinoids and a limited understanding of their mechanisms of action across different cell types. Our previous studies showed that treatment of organotypic human epidermis with the low toxicity UAB30 and UAB110 rexinoids resulted in increased steady-state levels of all-trans-retinoic acid (ATRA), the obligatory ligand of the RXR-RAR heterodimers. Here, we investigated the molecular mechanism underlying the increase in ATRA levels using a dominant negative RXRα that lacks the activation function 2 (AF-2) domain. The results demonstrated that overexpression of dnRXRα in human organotypic epidermis markedly reduced signaling by resident ATRA, suggesting the existence of endogenous RXR ligand, diminished the biological effects of UAB30 and UAB110 on epidermis morphology and gene expression, and nearly abolished the rexinoid-induced increase in ATRA levels. Global transcriptome analysis of dnRXRα-rafts in comparison to empty vector-transduced rafts showed that over 95% of the differentially expressed genes in rexinoid-treated rafts constitute direct or indirect ATRA-regulated genes. Thus, the biological effects of UAB30 and UAB110 are mediated through the AF-2 domain of RXRα with minimal side effects in human epidermis. As ATRA levels are known to be reduced in certain epithelial pathologies, treatment with UAB30 and UAB110 may represent a promising therapy for normalizing the endogenous ATRA concentration and signaling in epithelial tissues.
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| Overall design |
Transcriptomic profiling of control (CTR) and dominant negative RXRa (dnRXR) human skin rafts treated with UAB30 and UAB110 selective RXR agonists, using high throughput sequencing (Lexogen 3' QuantSeq).
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| Web link |
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0301447
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| Contributor(s) |
Halasz L, Berger WK, Nagy L |
| Citation(s) |
38557762 |
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| Submission date |
Sep 29, 2023 |
| Last update date |
Jul 02, 2024 |
| Contact name |
Laszlo Halasz |
| E-mail(s) |
laszlo.halasz@mssm.edu
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| Phone |
+17276416811
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| Organization name |
Mount Sinai Icahn School of Medicine
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| Department |
Department of Oncological Sciences
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| Lab |
Dr. Miriam Merad
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| Street address |
1470 Madison Avenue
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10029 |
| Country |
USA |
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| Platforms (1) |
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| Samples (24)
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| GSM7814571 |
Primary keratinocytes, Control untreated replicate 1 |
| GSM7814572 |
Primary keratinocytes, Control untreated replicate 2 |
| GSM7814573 |
Primary keratinocytes, Control untreated replicate 3 |
| GSM7814574 |
Primary keratinocytes, Control untreated replicate 4 |
| GSM7814575 |
Primary keratinocytes, Control UAB110 treated replicate 1 |
| GSM7814576 |
Primary keratinocytes, Control UAB110 treated replicate 2 |
| GSM7814577 |
Primary keratinocytes, Control UAB110 treated replicate 3 |
| GSM7814578 |
Primary keratinocytes, Control UAB110 treated replicate 4 |
| GSM7814579 |
Primary keratinocytes, Control UAB30 treated replicate 1 |
| GSM7814580 |
Primary keratinocytes, Control UAB30 treated replicate 2 |
| GSM7814581 |
Primary keratinocytes, Control UAB30 treated replicate 3 |
| GSM7814582 |
Primary keratinocytes, Control UAB30 treated replicate 4 |
| GSM7814583 |
Primary keratinocytes, Dominant negative RXRa untreated replicate 1 |
| GSM7814584 |
Primary keratinocytes, Dominant negative RXRa untreated replicate 2 |
| GSM7814585 |
Primary keratinocytes, Dominant negative RXRa untreated replicate 3 |
| GSM7814586 |
Primary keratinocytes, Dominant negative RXRa untreated replicate 4 |
| GSM7814587 |
Primary keratinocytes, Dominant negative RXRa UAB110 treated replicate 1 |
| GSM7814588 |
Primary keratinocytes, Dominant negative RXRa UAB110 treated replicate 2 |
| GSM7814589 |
Primary keratinocytes, Dominant negative RXRa UAB110 treated replicate 3 |
| GSM7814590 |
Primary keratinocytes, Dominant negative RXRa UAB110 treated replicate 4 |
| GSM7814591 |
Primary keratinocytes, Dominant negative RXRa UAB30 treated replicate 1 |
| GSM7814592 |
Primary keratinocytes, Dominant negative RXRa UAB30 treated replicate 2 |
| GSM7814593 |
Primary keratinocytes, Dominant negative RXRa UAB30 treated replicate 3 |
| GSM7814594 |
Primary keratinocytes, Dominant negative RXRa UAB30 treated replicate 4 |
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| Relations |
| BioProject |
PRJNA1022499 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE244387_count_table_CPM.txt.gz |
2.8 Mb |
(ftp)(http) |
TXT |
| GSE244387_count_table_raw.txt.gz |
956.0 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
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