The Double-Histone-Acetyltransferase Complex ATAC Is Essential for Mammalian Development

Abstract

Acetylation of the histone tails, catalyzed by histone acetyltransferases (HATs), is a well-studied process that contributes to transcriptionally active chromatin states. Here we report the characterization of a novel mammalian HAT complex, which contains the two acetyltransferases GCN5 and ATAC2 as well as other proteins linked to chromatin metabolism. This multisubunit complex has a similar but distinct subunit composition to that of the Drosophila ADA2A-containing complex (ATAC). Recombinant ATAC2 has a weak HAT activity directed to histone H4. Moreover, depletion of ATAC2 results in the disassembly of the complex, indicating that ATAC2 not only carries out an enzymatic function but also plays an architectural role in the stability of mammalian ATAC. By targeted disruption of the Atac2 locus in mice, we demonstrate for the first time the essential role of the ATAC complex in mammalian development, histone acetylation, cell cycle progression, and prevention of apoptosis during embryogenesis.

ACKNOWLEDGMENTS

We thank the following members of the Genentech core facilities: Nicole Kahoud, Sheila Bheddah, Jian Jiang, Julio Ramirez, Laszlo Komuves, Jeffrey Eastham-Anderson, Laurie Gilmour, Krista Bowman, and Alberto Estevez. We also thank Weilan Ye's group for initial analysis of Atac2 expression in mouse embryos and John Lowe and Kevin Leong for critical readings of the manuscript.

The KO mice were produced in a collaboration between Genentech and Lexicon Pharmaceuticals (The Woodlands, TX) to analyze the functions of about 500 secreted and transmembrane proteins.