title: Epigenomic reorganization of the clustered Hox genes in embryonic stem cells induced by retinoic acid.
abstract: Retinoic acid (RA) regulates clustered Hox gene expression during embryogenesis and is required to establish the anterior-posterior body plan. Using mutant embryonic stem cell lines deficient in the RA receptor γ (RARγ) or Hoxa1 3'-RA-responsive element, we studied the kinetics of transcriptional and epigenomic patterning responses to RA. RARγ is essential for RA-induced Hox transcriptional activation, and deletion of its binding site in the Hoxa1 enhancer attenuates transcriptional and epigenomic activation of both Hoxa and Hoxb gene clusters. The kinetics of epigenomic reorganization demonstrate that complete erasure of the polycomb repressive mark H3K27me3 is not necessary to initiate Hox transcription. RARγ is not required to establish the bivalent character of Hox clusters, but RA/RARγ signaling is necessary to erase H3K27me3 from activated Hox genes during embryonic stem cell differentiation. Highly coordinated, long range epigenetic Hox cluster reorganization is closely linked to transcriptional activation and is triggered by RARγ located at the Hoxa1 3'-RA-responsive element.
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Vasundhra
authors.initials: V
authors.lastname: Kashyap
authors.forename: Lorraine J
authors.initials: LJ
authors.lastname: Gudas
authors.forename: Fabienne
authors.initials: F
authors.lastname: Brenet
authors.forename: Patricia
authors.initials: P
authors.lastname: Funk
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Scandura
mesh_terms: D000818:Animals; D002875:Chromosomes; D053595:Embryonic Stem Cells / Q000166:cytology*; D057890:Epigenomics; D005801:Genes, Homeobox / Q000187:drug effects* / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D051379:Mice; D005810:Multigene Family; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000097768:Retinoic Acid Receptor gamma; D000099261:Homeobox A1 Protein
chemical_list: D018398:Homeodomain Proteins; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D000097768:Retinoic Acid Receptor gamma; D000099261:Homeobox A1 Protein