REGULATION OF GRANULOPOIESIS BY LYSINE ACETYLTRANSFERASE GCN5

Abstract

CCAAT/ENHANCER-BINDING PROTEIN ALPHA (C/EBPALPHA) IS AN ESSENTIAL TRANSCRIPTION FACTOR FOR MYELOID LINEAGE COMMITMENT. HERE WE DEMONSTRATE THAT ACETYLATION OF C/EBPALPHA AT LYSINE RESIDUES K298 AND K302, MEDIATED AT LEAST IN PART BY GENERAL CONTROL NON-DEREPRESSIBLE 5 (GCN5), IMPAIRS C/EBPALPHA DNA BINDING ABILITY AND MODULATES C/EBPALPHA TRANSCRIPTIONAL ACTIVITY. ACETYLATED C/EBPALPHA IS ENRICHED IN HUMAN MYELOID LEUKEMIA CELL LINES AND ACUTE MYELOID LEUKEMIA (AML) SAMPLES; AND DOWNREGULATED UPON GRANULOCYTE-COLONY STIMULATING FACTOR (G-CSF) - MEDIATED GRANULOCYTIC DIFFERENTIATION IN 32DCL3 CELLS. C/EBPALPHA MUTANTS THAT MIMIC ACETYLATION FAILED TO INDUCE GRANULOCYTIC DIFFERENTIATION IN C/EBPALPHA-DEPENDENT ASSAYS, IN BOTH CELL LINES AND IN PRIMARY HEMATOPOIETIC CELLS. OUR DATA UNCOVER GCN5 AS A NEGATIVE REGULATOR OF C/EBPALPHA AND DEMONSTRATE THE IMPORTANCE OF C/EBPALPHA ACETYLATION IN MYELOID DIFFERENTIATION.