Acetylation of C/EBPa inhibits its granulopoietic function

CCAAT/enhancer-binding protein alpha (C/EBP?) is an essential transcription factor for myeloid lineage commitment. Here we demonstrate that acetylation of C/EBP? at lysine residues K298 and K302, mediated at least in part by general control non-derepressible 5 (GCN5), impairs C/EBP? DNA-binding ability and modulates C/EBP? transcriptional activity. Acetylated C/EBPa 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/EBPa mutants that mimic acetylation failed to induce granulocytic differentiation in C/EBPa-dependent assays, in both cell lines and in primary hematopoietic cells. Our data uncover GCN5 as a negative regulator of C/EBPa and demonstrate the importance of C/EBPa acetylation in myeloid differentiation.