title: Epigenetic regulation of endothelial lineage committed genes in pro-angiogenic hematopoietic and endothelial progenitor cells.
abstract: BACKGROUND
  Proangiogenic hematopoietic and endothelial progenitor cells (EPCs) contribute to postnatal neovascularization, but the mechanisms regulating differentiation to the endothelial lineage are unclear.
  
  
  OBJECTIVE
  To elucidate the epigenetic control of endothelial gene expression in proangiogenic cells and EPCs.
  
  
  RESULTS
  Here we demonstrate that the endothelial nitric oxide synthase (eNOS) promoter is epigenetically silenced in proangiogenic cells (early EPCs), CD34(+) cells, and mesoangioblasts by DNA methylation and prominent repressive histone H3K27me3 marks. In order to reverse epigenetic silencing to facilitate endothelial commitment, we used 3-deazaneplanocin A, which inhibits the histone methyltransferase enhancer of zest homolog 2 and, thereby, reduces H3K27me3. 3-Deazaneplanocin A was not sufficient to increase eNOS expression, but the combination of 3-deazaneplanocin A and the histone deacetylase inhibitor Trichostatin A augmented eNOS expression, indicating that the concomitant inhibition of silencing histone modification and enhancement of activating histone modification facilitates eNOS expression. In ischemic tissue, hypoxia plays a role in recruiting progenitor cells. Therefore, we examined the effect of hypoxia on epigenetic modifications. Hypoxia modulated the balance of repressive to active histone marks and increased eNOS mRNA expression. The reduction of repressive H3K27me3 was associated with an increase of the histone demethylase Jmjd3. Silencing of Jmjd3 induced apoptosis and senescence in proangiogenic cells and inhibited hypoxia-mediated up-regulation of eNOS expression in mesoangioblasts.
  
  
  CONCLUSIONS
  These findings provide evidence that histone modifications epigenetically control the eNOS promoter in proangiogenic cells.
authors: Institute of Cardiovascular Regeneration, Internal Medicine III, University of Frankfurt, Germany.
authors: Kisho
authors: K
authors: Ohtani
authors: Georgios J
authors: GJ
authors: Vlachojannis
authors: Masamichi
authors: M
authors: Koyanagi
authors: Jes-Niels
authors: JN
authors: Boeckel
authors: Carmen
authors: C
authors: Urbich
authors: Ruxandra
authors: R
authors: Farcas
authors: Halvard
authors: H
authors: Bonig
authors: Victor E
authors: VE
authors: Marquez
authors: Andreas M
authors: AM
authors: Zeiher
authors: Stefanie
authors: S
authors: Dimmeler
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000235:genetics; D019070:Cell Lineage; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology*; D004790:Enzyme Induction / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D056484:Jumonji Domain-Containing Histone Demethylases / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D012333:RNA, Messenger; C012589:trichostatin A; C048460:3-deazaneplanocin; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C523761:Kdm6b protein, mouse; D000241:Adenosine