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

Abstract

contributed equally to this workIn Caenorhabditis elegans, histone acetyltransferase CBP-1 counteracts the repressive activity of the histone deacetylase HDA-1 to allow endoderm differentiation, which is speci®ed 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 ®ndings 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-speci®c gene transcription. Keywords: C.elegans embryonic development/CBP-1/ histone acetylase/histone deacetylase/transcriptional repression

-Catenin-Dependent Wnt Signaling in C. elegans: Teaching an Old Dog a New Trick

“…Conversely, in the Wntactivated daughter cell, the lower POP-1/TCF levels and higher SYS-1/b-catenin levels result in formation of a typical TCF/b-catenin bipartite transcription activator, which activates expression of target genes (Fig. 4B, right) (Calvo et al 2001;Zhao et al 2002;Maduro et al 2005;Shetty et al 2005;Arata et al 2006;Lam et al 2006;Huang et al 2007;Owraghi et al 2010). Molecular genetic manipulations that artificially alter the ratio of TCF to b-catenin between daughter cells lead to changes in gene expression or cell fate that are consistent with this model of Wnt pathway activation, switching the transcriptional behavior of TCF in the nucleus (Kidd et al 2005;Lam et al 2006;Huang et al 2007;Bertrand and Hobert 2009).…”

“…4B). In the anterior MS daughter nucleus, levels of POP-1/TCF are high, levels of the b-catenin SYS-1 are lower, and POP-1/TCF acts with transcriptional repressors such as histone deacetylase to silence expression of the endoderm-specific Wnt target genes end-1 and end-3 (Calvo et al 2001;Maduro et al 2002;Shetty et al 2005;Owraghi et al 2010). Conversely, in the -14, mom-1, mom-2, mom-5 mig-5, dsh-2, kin-19, gsk-3, mom-4, lit-1, apr-1, wrm-1, sys posterior E daughter, the levels of POP-1/TCF are lower and the levels of SYS-1 are high relative to their levels in the MS cell, and together these factors activate expression of the target genes end-1 and end-3, inducing that cell to adopt the endoderm fate (Huang et al 2007).…”

Wnt signaling through T-cell factor phosphorylation

“…enhancer of split) [27,28], CtBP [29,30], Kaiso [31][32][33], histone deacetylases (HDACs) and other factors, which maintain chromatin in the transcriptionally inactive state [34,35] and could mediate TCF-dependent transcriptional repression [28,[36][37][38][39]. The current model is that TCF proteins inhibit target genes when bound to Groucho/TLE corepressors, while association with β-catenin blocks these interactions and converts TCFs into transcriptional activators [1, 37,[40][41][42][43].…”

“…The proposed phosphorylation sites are located in the region of TCF3 that is responsible for Groucho binding (sometimes called the context-dependent region) [62,78]. Therefore, the alternative explanation is that the phosphorylation modulates the interaction of TCF3 with Groucho/TLE, HDACs or other cofactors [35,38,111,113,114,137,138], which may be necessary for optimal chromatin binding. Among other potential TCF3 regulators is Dishevelled, which shuttles to the nucleus [139], interacts with HIPK1 [104], and stabilizes β-catenin/TCF interactions [140].…”

An Extensive Requirement for Transcription Factor IID-specific TAF-1 in Caenorhabditis elegans Embryonic Transcription

“…end-1 regulation appears to be complex (Fig. 7A), involving MED proteins and the actions of CBP-1 and WNT signaling, which together relieve repression mediated by histone deacetylase (HDA-1) and POP-1 (29,41,44). In taf-5, taf-9, and taf-10(RNAi) embryos these genes were expressed at WT levels (Table I) (22,23).…”