Arginine methylation of the p30 C/EBPα oncoprotein regulates progenitor proliferation and myeloid differentiation
Linh T. Nguyen,
Karin Zimmermann,
Elisabeth Kowenz-Leutz,
Dorothea Dörr,
Anja Schütz,
Jörg Schönheit,
Alexander Mildner,
Achim Leutz
Affiliations
Linh T. Nguyen
Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Street 10, 13125 Berlin, Germany; BSIO Berlin School of Integrative Oncology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Karin Zimmermann
Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Street 10, 13125 Berlin, Germany
Elisabeth Kowenz-Leutz
Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Street 10, 13125 Berlin, Germany
Dorothea Dörr
Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Street 10, 13125 Berlin, Germany
Anja Schütz
Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Street 10, 13125 Berlin, Germany
Jörg Schönheit
Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Street 10, 13125 Berlin, Germany
Alexander Mildner
Institute of Biomedicine at University of Turku, Turku, Finland; InFLAMES Research Flagship, University of Turku, 20014 Turku, Finland
Achim Leutz
Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Street 10, 13125 Berlin, Germany; Corresponding author
Summary: The transcription factor CCAAT enhancer binding protein alpha (C/EBPα) is a master regulator of myelopoiesis. CEBPA encodes a long (p42) and a truncated (p30) protein isoform from a single mRNA. Mutations that abnormally enhance expression of p30 are associated with acute myelogenous leukemia (AML). We show by mutational analysis that three highly conserved arginine residues in the p30 C/EBPα N-terminus, previously found to be methylated, are involved in myeloid lineage commitment, progenitor proliferation, and differentiation. The conservative amino acid substitution with lysine that retains the amino acid side chain charge enhanced progenitor proliferation, while a non-conservative substitution with uncharged side chains (alanine, leucine) impaired proliferation and enhanced granulopoiesis. Analysis of protein interactions suggested that arginine methylation of p30 C/EBPα differentially determines interactions with SWI/SNF and MLL complexes. Pharmacological targeting of p30 C/EBPα arginine methylation may have clinical relevance in myeloproliferative and inflammatory diseases, in neutropenia, and in leukemic stem cells.
