title: Role of ZBP-89 in human globin gene regulation and erythroid differentiation.
abstract: The molecular mechanisms underlying erythroid-specific gene regulation remain incompletely understood. Closely spaced binding sites for GATA, NF-E2/maf, and CACCC interacting transcription factors play functionally important roles in globin and other erythroid-specific gene expression. We and others recently identified the CACCC-binding transcription factor ZBP-89 as a novel GATA-1 and NF-E2/mafK interacting partner. Here, we examined the role of ZBP-89 in human globin gene regulation and erythroid maturation using a primary CD34(+) cell ex vivo differentiation system. We show that ZBP-89 protein levels rise dramatically during human erythroid differentiation and that ZBP-89 occupies key cis-regulatory elements within the globin and other erythroid gene loci. ZBP-89 binding correlates strongly with RNA Pol II occupancy, active histone marks, and high-level gene expression. ZBP-89 physically associates with the histone acetyltransferases p300 and Gcn5/Trrap, and occupies common sites with Gcn5 within the human globin loci. Lentiviral short hairpin RNAs knockdown of ZBP-89 results in reduced Gcn5 occupancy, decreased acetylated histone 3 levels, lower globin and erythroid-specific gene expression, and impaired erythroid maturation. Addition of the histone deacetylase inhibitor valproic acid partially reverses the reduced globin gene expression. These findings reveal an activating role for ZBP-89 in human globin gene regulation and erythroid differentiation.
authors.affiliation: Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Woo
authors.forename: Jonghwan
authors.initials: J
authors.lastname: Kim
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.forename: Alan B
authors.initials: AB
authors.lastname: Cantor
mesh_terms: D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D041905:Erythroid Cells / Q000187:drug effects / Q000378:metabolism*; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004920:Erythropoiesis / Q000187:drug effects / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005914:Globins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D046228:Microarray Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D014157:Transcription Factors; C110951:ZNF148 protein, human; D014635:Valproic Acid; D005914:Globins