| Description |
As development progresses, cells become specialized and adopt a regional, cellular, tissue, or organ specific fate. This fate is directed by a specialized group of transcription factors called selector genes. Selector genes act at the top of a hierarchy and orchestrate expression of multiple target genes, thereby enacting developmental differentiation programs. One of these selector genes is the winged helix transcription factor FoxA. FoxA is essential for digestive tract development in all animals that it has been studied. For example, in the nematode Caenorhabditis elegans the FoxA homolog, pha-4, specifies pharyngeal, or foregut, cells. When it is disrupted, cells that would have become the pharynx develop as ectoderm. Despite the importance of FoxA proteins during foregut development, little is known about FoxA regulators and cofactors. To identify cofactors of FoxA, we performed a mutagenesis in C. elegans to screen for loci that interact genetically with pha-4. From this screen, 2 recessive and 11 dominant regulators of PHA-4 expression or activity were identified that suppress lethality associated with a partial loss of pha-4 function. Single nucleotide polymorphisms were used to map the 13 pha-4 suppressors, which showed that at least 9 genes were obtained from the screen. One of the dominant suppressors was identified as an allele of pha-4 itself, which demonstrated the effectiveness of the screen. Next, we looked in depth at a second pha-4 suppressor that was identified as a loss-of-function in the predicted DNA helicase ruvb-1. ruvb-1 is a known component of the Esa1/TIP60 and Swr1/p400 chromatin modifying and remodeling complex in eukaryotes. We investigated the role of chromatin remodeling during pharyngeal development and discovered that homologous components of the Esa1/TIP60 and Swr1/p400 remodeling complex act synergistically with pha-4 by associating the H2A histone variant, HTZ-1/H2AZ, to pharyngeal promoters. These findings are the first to demonstrate an in vivo requirement for chromatin remodeling during foregut development. Finally, we investigated additional phenotypes associated with the ruvb-1 mutant, which resemble mutations in the TOR kinase nutrient sensing pathway in C. elegans. The roles of ruvb-1 and pha-4 in nutrient sensing and metabolism during postembryonic development were examined. |
