title: Post transcriptional control of the epigenetic stem cell regulator PLZF by sirtuin and HDAC deacetylases.
abstract: BACKGROUND
  The transcriptional repressor promyelocytic leukemia zinc finger protein (PLZF) is critical for the regulation of normal stem cells maintenance by establishing specific epigenetic landscape. We have previously shown that CBP/p300 acetyltransferase induces PLZF acetylation in order to increase its deoxynucleotidic acid (DNA) binding activity and to enhance its epigenetic function (repression of PLZF target genes). However, how PLZF is inactivated is not yet understood.
  
  
  RESULTS
  In this study, we demonstrate that PLZF is deacetylated by both histone deacetylase 3 and the NAD+ dependent deacetylase silent mating type information regulation 2 homolog 1 (SIRT1). Unlike other PLZF-interacting deacetylases, these two proteins interact with the zinc finger domain of PLZF, where the activating CBP/p300 acetylation site was previously described, inducing deacetylation of lysines 647/650/653. Overexpression of histone deacetylase 3 (HDAC3) and SIRT1 is associated with loss of PLZF DNA binding activity and decreases PLZF transcriptional repression. As a result, the chromatin status of the promoters of PLZF target genes, involved in oncogenesis, shift from a heterochromatin to an open euchromatin environment leading to gene expression even in the presence of PLZF.
  
  
  CONCLUSIONS
  Consequently, SIRT1 and HDAC3 mediated-PLZF deacetylation provides for rapid control and fine-tuning of PLZF activity through post-transcriptional modification to regulate gene expression and cellular homeostasis.
authors.affiliation: Malaghan Institute for Medical Research, P.O. Box 7060, Wellington, New Zealand ; Division of Hematology/Oncology, Mount Sinai School of Medicine, New York, NY 10029 USA.
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: McConnell
authors.affiliation: INSERM UMRS-1131, Institut universitaire d'Hématologie, Université Paris Diderot, 1 avenue Claude Vellefaux, hôpital Saint-Louis, 75010 Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Durand
authors.affiliation: Wellcome Institute/Cancer Research UK, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR UK ; Biogen Idec, San Diego, CA 92122 USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Langley
authors.affiliation: INSERM UMRS-1131, Institut universitaire d'Hématologie, Université Paris Diderot, 1 avenue Claude Vellefaux, hôpital Saint-Louis, 75010 Paris, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Coste-Sarguet
authors.affiliation: Division of Hemato-oncology, Miller School of Medicine, Miami, FL 33136 USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Zelent
authors.affiliation: INSERM UMRS-1131, Institut universitaire d'Hématologie, Université Paris Diderot, 1 avenue Claude Vellefaux, hôpital Saint-Louis, 75010 Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Chomienne
authors.affiliation: Wellcome Institute/Cancer Research UK, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR UK.
authors.forename: Tony
authors.initials: T
authors.lastname: Kouzarides
authors.affiliation: Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 USA ; Division of Hematology/Oncology, Mount Sinai School of Medicine, New York, NY 10029 USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Licht
authors.affiliation: INSERM UMRS-1131, Institut universitaire d'Hématologie, Université Paris Diderot, 1 avenue Claude Vellefaux, hôpital Saint-Louis, 75010 Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Guidez
keywords: DNA methylation; Deacetylation; Epigenetic; Repression