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Molecular and Cellular Biology, August 2008, p. 5093-5105, Vol. 28, No. 16
0270-7306/08/$08.00+0     doi:10.1128/MCB.02202-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Mof (MYST1 or KAT8) Is Essential for Progression of Embryonic Development Past the Blastocyst Stage and Required for Normal Chromatin Architecture

The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia,¹ Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia²

Received 12 December 2007/ Returned for modification 4 April 2008/ Accepted 28 May 2008

Acetylation of histone tails is a hallmark of transcriptionally active chromatin. Mof (males absent on the first; also called MYST1 or KAT8) is a member of the MYST family of histone acetyltransferases and was originally discovered as an essential component of the X chromosome dosage compensation system in Drosophila. In order to examine the role of Mof in mammals in vivo, we generated mice carrying a null mutation of the Mof gene. All Mof-deficient embryos fail to develop beyond the expanded blastocyst stage and die at implantation in vivo. Mof-deficient cell lines cannot be derived from Mof^–/– embryos in vitro. Mof^–/– embryos fail to acetylate histone 4 lysine 16 (H4K16) but have normal acetylation of other N-terminal histone lysine residues. Mof^–/– cell nuclei exhibit abnormal chromatin aggregation preceding activation of caspase 3 and DNA fragmentation. We conclude that Mof is functionally nonredundant with the closely related MYST histone acetyltransferase Tip60. Our results show that Mof performs a different role in mammals from that in flies at the organism level, although the molecular function is conserved. We demonstrate that Mof is required specifically for the maintenance of H4K16 acetylation and normal chromatin architecture of all cells of early male and female embryos.

Published ahead of print on 9 June 2008.