The Mammalian Ortholog of Drosophila MOF That Acetylates Histone H4 Lysine 16 Is Essential for Embryogenesis and Oncogenesis

Abstract

The mammalian ortholog of the Drosophila MOF (males absent on the first) gene product is a histone H4 lysine 16-specific acetyltransferase. Recent studies have shown that depletion of human MOF (hMOF) in human cell lines leads to genomic instability, spontaneous chromosomal aberrations, cell cycle defects, altered nuclear morphology, reduced transcription of certain genes, and defective DNA damage response to ionizing radiation (IR). Here we show that MOF plays an essential role in mammals during embryogenesis and oncogenesis. Ablation of the mouse Mof gene (mMof) by gene targeting resulted in early embryonic lethality and cell death. Lethality correlated with the loss of H4 lysine 16 acetylation (H4K16ac) and could not be rescued by concomitant inactivation of ATM or p53. In comparison to primary cells or normal tissue, all immortalized human normal and tumor cell lines and primary tumors demonstrated similar or elevated hMOF and H4K16ac levels. Accordingly, MOF overexpression correlated with increased cellular proliferation, oncogenic transformation, and tumor growth. Thus, these data reveal that the acetylation of histone H4 at K16 by MOF is an epigenetic signature of cellular proliferation common to both embryogenesis and oncogenesis and that MOF is an essential factor for embryogenesis and oncogenesis.

ACKNOWLEDGMENTS

We thank J. Michael White and Raju Kucherlapati for their advice and support. Thanks are due to Manel Esteller and Clayton Hunt for their suggestions and comments on the manuscript and to L. Mao for providing us with the samples of mRNA from tumor and normal tissue samples.

This investigation was supported by funds from NIH (CA123232 and CA10445), Department of Defense, and the Department of Radiation Oncology of the Washington University School of Medicine to T.K.P., and NCI grant PO1 CA97403 (Project 5) to T.L.