title: Acetylation of C/EBPε is a prerequisite for terminal neutrophil differentiation.
abstract: C/EBPε, a member of the CCAAT/enhancer binding protein (C/EBP) family of transcription factors, is exclusively expressed in myeloid cells and regulates transition from the promyelocytic stage to the myelocytic stage of neutrophil development, being indispensable for secondary and tertiary granule formation. Knowledge concerning the functional role of C/EBPε posttranslational modifications is limited to studies concerning phosphorylation and sumoylation. In the current study, using ectopic expression and ex vivo differentiation of CD34(+) hematopoietic progenitor cells, we demonstrate that C/EBPε is acetylated, which was confirmed by mass spectrometry analysis, identifying 4 acetylated lysines in 3 distinct functional domains. Regulation of C/EBPε acetylation levels by the p300 acetyltransferase and the sirtuin 1 deacetylase controls transcriptional activity, which can at least in part be explained by modulation of DNA binding. During neutrophil development, acetylation of lysines 121 and 198 were found to be crucial for terminal neutrophil differentiation and the expression of neutrophil-specific granule proteins, including lactoferrin and collagenase. Taken together, our data illustrate a critical role for acetylation in the functional regulation of C/EBPε activity during terminal neutrophil development.
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, and Division of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands;
authors.forename: Marije
authors.initials: M
authors.lastname: Bartels
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, and Division of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands;
authors.forename: Anita M
authors.initials: AM
authors.lastname: Govers
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, and.
authors.forename: Veerle
authors.initials: V
authors.lastname: Fleskens
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, and.
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Lourenço
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, and.
authors.forename: Cornelieke E
authors.initials: CE
authors.lastname: Pals
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, and.
authors.forename: Stephin J
authors.initials: SJ
authors.lastname: Vervoort
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands;
authors.forename: Rogier
authors.initials: R
authors.lastname: van Gent
authors.affiliation: Department of Metabolic Diseases, University Medical Center Utrecht, Utrecht, The Netherlands; and.
authors.forename: Arjan B
authors.initials: AB
authors.lastname: Brenkman
authors.affiliation: Division of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands;
authors.forename: Marc B
authors.initials: MB
authors.lastname: Bierings
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Ackerman
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, and Division of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands;
authors.forename: Jorg
authors.initials: J
authors.lastname: van Loosdregt
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, and Division of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands;
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coffer
mesh_terms: D000107:Acetylation; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D017364:Collagenases / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007781:Lactoferrin / Q000378:metabolism; D008239:Lysine / Q000737:chemistry; D038042:Myelopoiesis; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D017364:Collagenases; D007781:Lactoferrin; D008239:Lysine; D011993:Recombinant Fusion Proteins; D056564:Sirtuin 1; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C490098:LTF protein, human; C070790:CEBPE protein, human; C447939:SIRT1 protein, human