A POP-1 repressor complex restricts inappropriate cell type-specific gene transcription during Caenorhabditis elegans embryogenesis.

In Caenorhabditis elegans, histone acetyltransferase CBP-1 counteracts the repressive activity of the histone deacetylase HDA-1 to allow endoderm differentiation, which is specified by the E cell. In the sister MS cell, the endoderm fate is prevented by the action of an HMG box-containing protein, POP-1, through an unknown mechanism. In this study, we show that CBP-1, HDA-1 and POP-1 converge on end-1, an initial endoderm-determining gene. In the E lineage, an essential function of CBP-1 appears to be the activation of end-1 transcription. We further identify a molecular mechanism for the endoderm-suppressive effect of POP-1 in the MS lineage by demonstrating that POP-1 functions as a transcriptional repressor that inhibits inappropriate end-1 transcription. We provide evidence that POP-1 represses transcription via the recruitment of HDA-1 and UNC-37, the C.elegans homolog of the co-repressor Groucho. These findings demonstrate the importance of the interplay between acetyltransferases and deacetylases in the regulation of a critical cell fate-determining gene during development. Furthermore, they identify a strategy by which concerted actions of histone deacetylases and other co-repressors ensure maximal repression of inappropriate cell type-specific gene transcription.

Stimulation of p300-mediated transcription by the kinase MEKK1.

p300 and CREB-binding protein (CBP) are related transcriptional coactivators that possess histone acetyltransferase activity. Inactivation of p300/CBP is part of the mechanism by which adenovirus E1A induces oncogenic transformation of cells. Recently, the importance of p300/CBP has been demonstrated directly in several organisms including mouse, Drosophila, and Caenorhabditis elegans where p300/CBP play an indispensable role in differentiation, in patterning, and in cell fate determination and proliferation during development. CBP/p300s are modified by phosphorylation during F9 cell differentiation as well as adenovirus infection, suggesting that phosphorylation may play a role in the regulation of p300/CBP activity. Here we show that the mitogen-activated/extracellular response kinase kinase 1 (MEKK1) enhances p300-mediated transcription. We identify several domains within p300 that can respond to MEKK1-induced transcriptional activation. Interestingly, activation of p300-mediated transcription by MEKK1 does not appear to require the downstream kinase JNK and may involve either a direct phosphorylation of p300 by MEKK1 or by other non-JNK MEKK1-directed downstream kinases. Finally, we present evidence that p300 is important for MEKK1 to induce apoptosis. Taken together, these results identify MEKK1 as a kinase that is likely to be involved in the regulation of the transactivation potential of p300 and support a role of p300 in MEKK1-induced apoptosis.