title: Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis.
abstract: BACKGROUND
  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. However, little is known about where RAR binds to the genome or how it selects target sites.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Shaun
authors.initials: S
authors.lastname: Mahony
authors.forename: Esteban O
authors.initials: EO
authors.lastname: Mazzoni
authors.forename: Scott
authors.initials: S
authors.lastname: McCuine
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
authors.forename: Hynek
authors.initials: H
authors.lastname: Wichterle
authors.forename: David K
authors.initials: DK
authors.lastname: Gifford
mesh_terms: D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D008024:Ligands; D055495:Neurogenesis / Q000502:physiology*; D011485:Protein Binding; D012319:RNA Polymerase II / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D008024:Ligands; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D012319:RNA Polymerase II