Loss of Gcn5/2 leads to increased apoptosis and mesodermal defects during mouse development

Histone acetyltransferases regulate transcription, but little is known abou t the role of these enzymes in developmental processes. Gcn5 (encoded by Gc n5/2) and Pcaf. mouse histone acetyltransferases. share similar sequences a nd enzymatic activities(1). Both interact with p300 and CBP (encoded by Ep3 00 and Crebbp, respectively), two other histone acetyltransferases that int egrate multiple signalling pathways(1). Pcaf is thought to participate in m any of the cellular processes regulated by p300/CBP (refs 2-8). but the fun ctions of Gcn5 are unknown in mammalian cells. Here we show that the gene P caf is dispensable in mice. In contrast. Gcn5/2-null embryos die during emb ryogenesis. These embryos develop normally to 7.5 days post coitum (d.p.c.) . but their growth is severely retarded by 8.5 d.p.c. and they fail to form dorsal mesoderm lineages, including chordamesoderm and paraxial mesoderm. Differentiation of extra-embryonic and cardiac mesoderm seems to be unaffec ted. Loss of the dorsal mesoderm lineages is due to a high incidence of apo ptosis in the Gcn5/2 mutants that begins before the onset of morphological abnormality. Embryos null for both Gcn5/2 and Pcaf show even more severe de fects, indicating that these histone acetyltransferases have overlapping fu nctions during embryogenesis. Our studies are the first to demonstrate that specific acetyltransferases are required for cell survival and mesoderm fo rmation during mammalian development.