Mammalian
p300 and its related protein CBP are transcriptional cofactors and targets of adenovirus E1A. Inactivation of
p300/CBP is critical for E1A to induce oncogenic transformation of primary rodent cells, and to inhibit differentiation.
p300/CBP serve as cofactors for a large number of sequence-specific DNA-binding transcription factors and function to integrate transcriptional and signalling events in cells. Biochemically,
p300/CBP has recently been shown to possess histone acetyltranferase activity. Here, using a reverse genetic approach analagous to RNA antisense, we block the expression of a
p300/CBP homolog, R10E11.1, which we refer to as Ce-
p300. The resulting embryos lack mesodermal, endodermal and epidermal cell fates, arrest development with approximately twice the normal number of embryonic cells, but do exhibit evidence of neuronal differentiation and apoptosis. The phenotypic effect of blocking Ce-
p300 expression is consistent with a block in the activity of two early embryonic cell fate-determining transcription factors, SKN-1 and PAL-1, raising the possiblity that these factors utilize
p300 to activate differentiation pathways. RPD3/RbAp48 are components of a conserved histone deacetylase complex. We show that inhibition of these proteins in C. elegans reverse the block in mesoderm and endoderm differentiation caused by
p300 inhibition, and also restore endoderm differentiation in the SKN-1 mutant embryos. These observations suggest that
p300 may be recruited by transcription factors such as SKN-1 and PAL-1 to antagonize the function of RPD3 and RbAp48. Such a mechanism underlies at least in part the biological functions of
p300.