title: Regulation of primitive hematopoiesis by class I histone deacetylases.
abstract: BACKGROUND
  Histone deacetylases (HDACs) regulate multiple developmental processes and cellular functions. However, their roles in blood development have not been determined, and in Xenopus laevis a specific function for HDACs has yet to be identified. Here, we employed the class I selective HDAC inhibitor, valproic acid (VPA), to show that HDAC activity is required for primitive hematopoiesis.
  
  
  RESULTS
  VPA treatment during gastrulation resulted in a complete absence of red blood cells (RBCs) in Xenopus tadpoles, but did not affect development of other mesodermal tissues, including myeloid and endothelial lineages. These effects of VPA were mimicked by Trichostatin A (TSA), a well-established pan-HDAC inhibitor, but not by valpromide, which is structurally similar to VPA but does not inhibit HDACs. VPA also caused a marked, dose-dependent loss of primitive erythroid progenitors in mouse yolk sac explants at clinically relevant concentrations. In addition, VPA treatment inhibited erythropoietic development downstream of bmp4 and gata1 in Xenopus ectodermal explants.
  
  
  CONCLUSIONS
  These findings suggest an important role for class I HDACs in primitive hematopoiesis. Our work also demonstrates that specific developmental defects associated with exposure to VPA, a significant teratogen in humans, arise through inhibition of class I HDACs.
authors.affiliation: Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Rishita R
authors.initials: RR
authors.lastname: Shah
authors.forename: Anne
authors.initials: A
authors.lastname: Koniski
authors.forename: Mansi
authors.initials: M
authors.lastname: Shinde
authors.forename: Shelby A
authors.initials: SA
authors.lastname: Blythe
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Fass
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.forename: James
authors.initials: J
authors.lastname: Palis
authors.forename: Peter S
authors.initials: PS
authors.lastname: Klein
mesh_terms: D000818:Animals; D017931:DNA Primers / Q000235:genetics; D015672:Erythroid Precursor Cells / Q000187:drug effects; D005775:Gastrula / Q000187:drug effects*; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D015151:Immunoblotting; D017403:In Situ Hybridization; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D014635:Valproic Acid / Q000494:pharmacology; D014982:Xenopus laevis / Q000196:embryology*; D015017:Yolk Sac / Q000166:cytology
chemical_list: D017931:DNA Primers; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D014635:Valproic Acid; D006655:Histone Deacetylases