title: Identification of NuRSERY, a new functional HDAC complex composed by HDAC5, GATA1, EKLF and pERK present in human erythroid cells.
abstract: To clarify the role of HDACs in erythropoiesis, expression, activity and function of class I (HDAC1, HDAC2, HDAC3) and class IIa (HDAC4, HDAC5) HDACs during in vitro maturation of human erythroblasts were compared. During erythroid maturation, expression of HDAC1, HDAC2 and HDAC3 remained constant and activity and GATA1 association (its partner of the NuRD complex), of HDAC1 increased. By contrast, HDAC4 content drastically decreased and HDAC5 remained constant in content but decreased in activity. In erythroid cells, pull down experiments identified the presence of a novel complex formed by HDAC5, GATA1, EKLF and pERK which was instead undetectable in cells of the megakaryocytic lineage. With erythroid maturation, association among HDAC5, GATA1 and EKLF persisted but levels of pERK sharply decreased. Treatment of erythroleukemic cells with inhibitors of ERK phosphorylation reduced by >90% the total and nuclear content of HDAC5, GATA1 and EKLF, suggesting that ERK phosphorylation is required for the formation of this complex. Based on the function of class IIa HDACs as chaperones of other proteins to the nucleus and the erythroid-specificity of HDAC5 localization, this novel HDAC complex was named nuclear remodeling shuttle erythroid (NuRSERY). Exposure of erythroid cells to the class II-selective HDAC inhibitor (HDACi) APHA9 increased γ/(γ+β) globin expression ratios (Mai et al., 2007), suggesting that NuRSERY may regulate globin gene expression. In agreement with this hypothesis, exposure of erythroid cells to APHA9 greatly reduced the association among HDAC5, GATA1 and EKLF. Since exposure to APHA9 did not affect survival rates or p21 activation, NuRSERY may represent a novel, possibly less toxic, target for epigenetic therapies of hemoglobinopaties and other disorders.
authors.affiliation: Hematology/Oncology, Mount Sinai School of Medicine, One Gustave L. Levy, New York, NY, USA.
authors.forename: Lilian
authors.initials: L
authors.lastname: Varricchio
authors.affiliation: Institute of Genetics and Biophysics, "Adriano Buzzati Traverso", IGB, P. Castellino 111, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Dell'Aversana
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, L. De Crecchio 7, Naples, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Nebbioso
authors.affiliation: Cell Biology and Neuroscience, Istituto Superiore di Sanita', Viale Regina Elena 299, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Migliaccio
authors.affiliation: Institute of Genetics and Biophysics, "Adriano Buzzati Traverso", IGB, P. Castellino 111, Italy; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, L. De Crecchio 7, Naples, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università "Sapienza", P.le A. Moro 5, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.affiliation: Centro Nazionale Sangue, via Giano della Bella 27, Rome, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Grazzini
authors.affiliation: Developmental and Regenerative Biology, Mount Sinai School of Medicine, One Gustave L. Levy, New York, NY, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Bieker
authors.affiliation: Hematology/Oncology, Mount Sinai School of Medicine, One Gustave L. Levy, New York, NY, USA; Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita', Viale Regina Elena 299, Italy. Electronic address: annarita.migliaccio@mssm.edu.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Migliaccio
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004900:Erythroblasts / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D041905:Erythroid Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008533:Megakaryocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D050982:GATA1 Transcription Factor; D006655:Histone Deacetylases; D051741:Kruppel-Like Transcription Factors; D019892:eIF-2 Kinase; C494688:GATA1 protein, human; C080774:erythroid Kruppel-like factor; C404500:HDAC5 protein, human
keywords: EKLF; Erythropoiesis; GATA1; Histone deacetylase inhibitors; Histone deacetylases