Abstract
BackgroundAmong its many roles in development, retinoic acid determines the anterior-posterior identity of differentiating motor neurons by activating retinoic acid receptor (RAR)-mediated transcription. RAR is thought to bind the genome constitutively, and only induce transcription in the presence of the retinoid ligand. However, little is known about where RAR binds to the genome or how it selects target sites.ResultsWe tested the constitutive RAR binding model using the retinoic acid-driven differentiation of mouse embryonic stem cells into differentiated motor neurons. We find that retinoic acid treatment results in widespread changes in RAR genomic binding, including novel binding to genes directly responsible for anterior-posterior specification, as well as the subsequent recruitment of the basal polymerase machinery. Finally, we discovered that the binding of transcription factors at the embryonic stem cell stage can accurately predict where in the genome RAR binds after initial differentiation.ConclusionsWe have characterized a ligand-dependent shift in RAR genomic occupancy at the initiation of neurogenesis. Our data also suggest that enhancers active in pluripotent embryonic stem cells may be preselecting regions that will be activated by RAR during neuronal differentiation.
Highlights
Among its many roles in development, retinoic acid determines the anterior-posterior identity of differentiating motor neurons by activating retinoic acid receptor (RAR)-mediated transcription
RAR chromatin immunoprecipitation (ChIP)-seq profiles direct genomic interactions during early differentiation Using a pan-RAR antibody, we profiled the genomewide occupancy of RAR isoforms in differentiating embryoid bodies after 8 hours of exposure to Retinoic acid (RA), finding significant ChIP-seq enrichment at 1,924 sites
We find that high-similarity hormone response element motifs occur at RAR ChIP-enriched sites at a higher rate than that observed in published ChIP-seq studies of other nuclear hormone receptors such as ERa, Esrrb, and Nr5a2 [10,24,25,26] (Additional file 1)
Summary
Among its many roles in development, retinoic acid determines the anterior-posterior identity of differentiating motor neurons by activating retinoic acid receptor (RAR)-mediated transcription. RAR is thought to bind the genome constitutively, and only induce transcription in the presence of the retinoid ligand. Fate determination, and differentiation are influenced by the external signals cells receive. While these external signals can take the form of steroid hormones, protein growth factors, or other molecules, their presence is typically communicated by signalresponsive transcription factors (TFs). The effect of a signal on gene expression, and on cell fate, depends on where such TFs bind to the genome.
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