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Acetylation of C/EBPα Inhibits its Granulopoietic Function (Nature Commun, Mar 2016)

Bararia D1,2,3,4,5,6, Kwok HS1,7, Welner RS8,9, Numata A1, Sárosi MB10, Yang H1, Wee S11, Tschuri S3,4,5,6, Ray D12, Weigert O3,4,5,6, Levantini E2,8,13, Ebralidze AK2,8, Gunaratne J11,14, Tenen DG1,2,8

1Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore.
2Dana Farber/Harvard Cancer Center, Boston, Massachusetts 02215, USA.
3Department of Internal Medicine III, University Hospital of the Ludwig-Maximilians-University Munich, Munich D-81377, Germany.
4Experimentelle Leukämie-und Lymphomforschung (ELLF), LMU, Munich D-81377, Germany.
5German Cancer Consortium (DKTK), Heidelberg D-69120, Germany.
6German Cancer Research Center (DKFZ), Heidelberg D-69120, Germany.
7National University of Singapore Graduate School for Integrative Sciences and Engineering, Singapore 117456, Singapore.
8Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
9University of Alabama at Birmingham, Department of Medicine, Division of Hematology/Oncology, Birmingham, Alabama 35294, USA.
10Institute of Inorganic Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Leipzig D-04103, Germany.
11Translational Biomedical Proteomics Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore.
12Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
13Institute of Biomedical Technologies, National Research Council (CNR), Pisa 56124, Italy.
14Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore.

CCAAT/enhancer-binding protein alpha (C/EBPα) is an essential transcription factor for myeloid lineage commitment. Here we demonstrate that acetylation of C/EBPα at lysine residues K298 and K302, mediated at least in part by general control non-derepressible 5 (GCN5), impairs C/EBPα DNA-binding ability and modulates C/EBPα transcriptional activity. Acetylated C/EBPα is enriched in human myeloid leukaemia cell lines and acute myeloid leukaemia (AML) samples, and downregulated upon granulocyte-colony stimulating factor (G-CSF)- mediated granulocytic differentiation of 32Dcl3 cells. C/EBPα mutants that mimic acetylation failed to induce granulocytic differentiation in C/EBPα-dependent assays, in both cell lines and in primary hematopoietic cells. Our data uncover GCN5 as a negative regulator of C/EBPα and demonstrate the importance of C/EBPα acetylation in myeloid differentiation.