title: miRNA-130a regulates C/EBP-ε expression during granulopoiesis.
abstract: CCAAT/enhancer binding protein-ε (C/EBP-ε) is considered a master transcription factor regulating terminal neutrophil maturation. It is essential for expression of secondary granule proteins, but it also regulates proliferation, cell cycle, and maturation during granulopoiesis. Cebpe(-/-) mice have incomplete granulocytic differentiation and increased sensitivity toward bacterial infections. The amount of C/EBP-ε messenger RNA (mRNA) increases with maturation from myeloblasts with peak level in myelocytes (MC)/metamyelocytes (MM), when the cells stop proliferating followed by a decline in more mature cells. In contrast, C/EBP-ε protein is virtually detectable only in the MC/MM population, indicating that expression in more immature cells could be inhibited by microRNAs (miRNAs). We found that miRNA-130a (miR-130a) regulates C/EBP-ε protein expression in both murine and human granulocytic precursors. Overexpression of miR-130a in a murine cell line downregulated C/EBP-ε protein and lactoferrin (Ltf), cathelicidin antimicrobial protein (Camp), and lipocalin-2 (Lcn2) mRNA expression giving rise to cells with a more immature phenotype, as seen in the Cebpe(-/-) mouse. Introduction of a C/EBP-ε mRNA without target site for miR-130a restored both C/EBP-ε production, expression of Camp and Lcn2, and resulted in the cells having a more mature phenotype. We conclude that miR-130a is important for the regulation of the timed expression of C/EBP-ε during granulopoiesis.
authors.affiliation: The Granulocyte Research Laboratory and.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Larsen
authors.forename: Mattias
authors.initials: M
authors.lastname: Häger
authors.forename: Andreas
authors.initials: A
authors.lastname: Glenthøj
authors.forename: Fazila
authors.initials: F
authors.lastname: Asmar
authors.forename: Stine N
authors.initials: SN
authors.lastname: Clemmensen
authors.forename: Helena
authors.initials: H
authors.lastname: Mora-Jensen
authors.forename: Niels
authors.initials: N
authors.lastname: Borregaard
authors.forename: Jack B
authors.initials: JB
authors.lastname: Cowland
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D042381:Granulocyte Precursor Cells / Q000502:physiology; D006098:Granulocytes / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D019891:Leukopoiesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology*; D041681:NIH 3T3 Cells
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C554019:MIRN130 microRNA, human; D035683:MicroRNAs; C070790:CEBPE protein, human