RED CELLS, IRON, AND ERYTHROPOIESIS Protein kinase D-HDAC5 signaling regulates erythropoiesis and contributes to erythropoietin cross-talk with GATA1

In red cell development, the differentia-tion program directed by the transcrip-tional regulator GATA1 requires signaling by the cytokine erythropoietin, but the mechanistic basis for this signaling re-quirement has remained unknown. Here we show that erythropoietin regulates GATA1 through protein kinase D activa-tion, promoting histone deacetylase 5 (HDAC5) dissociation from GATA1, and subsequent GATA1 acetylation. Mice defi-cient for HDAC5 show resistance to ane-mic challenge and altered marrow respon-siveness to erythropoietin injections. In ex vivo studies, HDAC5/ progenitors display enhanced entry into and passage through the erythroid lineage, as well as evidence of erythropoietin–independent differentiation. These results reveal a mo-lecular pathway that contributes to cyto-kine regulation of hematopoietic differen-tiation and offer a potential mechanism for fine tuning of lineage-restricted tran-scription factors by lineage-specific cyto-kines. (Blood. 2012;120(20):4219-4228