miRNA-130a regulates C/EBP-ε expression during granulopoiesis

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 in...

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Bibliographic Details
Published in:Blood 2014-02, Vol.123 (7), p.1079-1089
Main Authors: Larsen, Maria T., Häger, Mattias, Glenthøj, Andreas, Asmar, Fazila, Clemmensen, Stine N., Mora-Jensen, Helena, Borregaard, Niels, Cowland, Jack B.
Format: Article
Language:English
Subjects:
Animals
CCAAT-Enhancer-Binding Proteins - genetics
Cell Differentiation - genetics
Cells, Cultured
Gene Expression Regulation
Granulocyte Precursor Cells - physiology
Granulocytes - physiology
HEK293 Cells
Humans
Leukopoiesis - genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
MicroRNAs - physiology
NIH 3T3 Cells
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Summary: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. •miRNA-130a is expressed in myeloblasts and promyelocytes and inhibits translation of CEBPE mRNA encoding transcription factor C/EBP-ε.•Regulation of CEBPE mRNA by miRNA-130a is required for timed expression of secondary granule proteins and cell cycle exit.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2013-08-523233