GCN5 and p300 share essential functions during early embryogenesis

Abstract

Previous studies revealed that deletion of genes encoding the histone acetyltransferases GCN5, p300, or CBP results in embryonic lethality in mice. PCAF and GCN5 physically interact with p300 and CBP in vitro. To determine whether these two groups of histone acetyltransferases interact functionally in vivo, we created mice lacking one or more alleles of p300, GCN5, or PCAF. As expected, we found that mice heterozygous for any single null allele are viable. The majority of GCN5 ϩ/Ϫ p300 ϩ/Ϫ mice also survive to adulthood with no apparent abnormalities. However, ϳ25% of these mice die before birth. These embryos are developmentally stunted and exhibit increased apoptosis compared with wild-type or single GCN5 ϩ/Ϫ or p300 ϩ/Ϫ littermates at embryonic day 8.5. In contrast, no abnormalities were observed in PCAF Ϫ/Ϫ p300 ϩ/Ϫ mice. Of interest, we find that p300 protein levels vary in different mouse genetic backgrounds, which likely contributes to the incomplete penetrance of the abnormal phenotype of GCN5 ϩ/Ϫ p300 ϩ/Ϫ mice. Our data indicate that p300 cooperates specifically with GCN5 to provide essential functions during early embryogenesis. Developmental Dynamics 233:1337-1347, 2005.

Conditional Knockout Mice Reveal Distinct Functions for the Global Transcriptional Coactivators CBP and p300 in T-Cell Development

“…Together, the data support the view that there are intrinsic differences in the tumor suppressor functions of CBP and p300, even though the contributing environmental and genetic factors required for T-cell lymphomagenesis in the absence of CBP are unclear and somewhat variable. In this regard, it has recently been shown that p300 levels can vary in different mouse strains, suggesting that the combined dosage of CBP and p300 protein may also fluctuate and lead to variable phenotypic penetrance (158).…”

“…So other cofactors may only be able to compensate under a limited number of situations. The identities of such factors are unknown, although recent genetic studies demonstrate that the combined dosage of various histone acetyltransferase proteins harboring bromodomains (p300 and Gcn5, and p300 and P/CAF) are not generally limiting for mouse development (158).…”

Proper expression of the Gcn5 histone acetyltransferase is required for neural tube closure in mouse embryos

“…Interestingly, Gcn5 and PCAF proteins each interact physically with p300 and CBP (Xu et al, 1998). Although mice heterozygous for either a Gcn5 or a p300 null allele are viable, Gcn5 p300 double heterozygotes exhibit reduced viability, confirming these HATs share some essential functions (Phan et al, 2005).…”

“…Our previous work indicated that Gcn5 is required for early embryogenesis and that it shares functions with p300 during development (Xu et al, 2000;Phan et al, 2005). We have also shown that mouse embryos homozygous for point mutations in Gcn5 that eliminate its acetyltransferase activity exhibit defects in cranial neural tube closure and die by E16.0 (Bu et al, 2007).…”

Developmental potential of Gcn5−/− embryonic stem cells in vivo and in vitro

“…Mice heterozygous for the Gcn5 null allele are viable, as are most mice heterozygous for a p300 deletion. However, a substantial portion of mice heterozygous both Gcn5 and p300 null alleles die in utero, indicating that a critical dosage of these two HATs must be maintained during development (Phan et al, 2005).…”