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Synergistic activation of RARb and RARg-driven programs restores cell-types specialization during stem cell differentiation

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE204816 | GEO | 2022/11/10

REPOSITORIES: GEO

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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.

2021-02-10 | PXD018172 | Pride

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

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2012-12-31 | E-GEOD-43221 | biostudies-arrayexpress

Cistrome profiles of Retinoids x Receptor alpha (RXR?) , Retinoic Acid Receptor alpha (RAR?), and Retinoic Acid Receptor beta (RAR?) in livers of mice treated by control and retionic acid-containing diet

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2014-01-23 | E-GEOD-53736 | biostudies-arrayexpress

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Fight-or-flight responses require augmentation of Ca2+ influx via Rad phosphorylation

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2022-09-26 | PXD033492 | Pride

Dissecting the retinoid-induced differentiation of F9 embryonal stem cells by integrative genomics [mRNA profiling]

Project description:Retinoic acid (RA) triggers physiological processes by activating heterodimeric transcription factors comprising retinoic acid (RARa,b,g) and retinoid X (RXRa,b,g) receptors. How a single signal induces highly complex temporally controlled networks that ultimately orchestrate physiological processes is unclear. Using an RA-inducible differentiation model we defined the temporal changes in the genome-wide binding patterns of RARg and RXRa and correlated them with transcription regulation. Unexpectedly, both receptors displayed a highly dynamic binding, with different RXRa heterodimers targeting identical loci. Comparison of RARg and RXRa co-binding at RA-regulated genes identified putative RXRa-RARg target genes that were validated with subtype-selective agonists. Gene regulatory decisions during differentiation were inferred from transcription factor target gene information and temporal gene expression. This analysis revealed 6 distinct co-expression paths of which RXRa-RARg is associated with transcription activation, while Sox2 and Egr1 were predicted to regulate repression. Finally, RXRa-RARg regulatory networks were reconstructed through integration of functional co-citations. Our analysis provides a dynamic view of RA signalling during cell differentiation, reveals RA heterodimer dynamics and promiscuity, and predicts decisions that diversify the RA signal into distinct gene-regulatory programs. Transcriptional activity in F9 cells treated with different retinoic acid receptor (RAR) agonists; like all-trans retinoic acid (ATRA), BMS961 (RARg-specific), BMS753 (RARa-specific) or BMS641(RARb-specific); has been evaluated at different time-points (2, 6, 24, 48h) and compared with that found under Ethanol-vehicle treatment conditions (48h treatment).

2011-10-10 | E-GEOD-30537 | biostudies-arrayexpress

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2010-06-09 | GSE22213 | GEO

Identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics [RNA-seq]

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