HATs, KATs, and Grannies: "Histone" acetyltransferase function in Hematopoietic Stem Cell maintenance and myelopoiesis

With Daniel G. Tenen, MD  Professor of Medicine at Harvard Medical School and Director of the Blood Program of the Harvard Stem Cell Institute; Distinguished Professor, Department of Medicine, National University of Singapore; and Director, Cancer Science Institute of Singapore.

"Histone" acetyltransferases (HATs) are actually lysine acetyltransferases (KATs), with targets other than histone proteins. CCAAT/enhancer-binding protein alpha (C/EBPa) is an essential transcription factor for myeloid lineage commitment. Here we demonstrate that acetylation of C/EBPa at lysine residues K298 and K302, mediated at least in part the KAT GCN5, impairs C/EBPa DNA-binding ability and modulates C/EBPa transcriptional activity. Acetylated C/EBPa 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 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.

The MSYT family KAT, Tat-Interactive Protein 60 (TIP60), plays a crucial role in cellular activities, including DNA repair, apoptosis, cell cycle arrest, and transcriptional regulation, and has been characterized as a tumor suppressor. Here we demonstrate TIP60 is essential for the maintenance of both fetal and adult mouse hematopoietic stem and progenitor cells (HSPC). Conditional deletion of TIP60 in hematopoietic cells leads to rapid HSPC depletion. The cells undergo apoptosis, demonstrating aberrant mitosis and increased DNA damage. Genome-wide gene expression profiling and chromatin immunoprecipitation with deep sequencing reveals that c-Myc and N-myc target genes are directly regulated by TIP60 in HSPC, accompanied by acetylation of H3K27 and H4K16 in the promoters. Therefore, TIP60 is required for HSC maintenance through the Myc transcriptional network, revealing a role for TIP60 as a general transcriptional regulator for cell survival and proliferation.