Diverse Chromatin Remodeling Genes Antagonize the Rb-Involved SynMuv Pathways in C. elegans

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Abstract
In Caenorhabditis elegans, vulval cell-fate specification involves the activities of multiple signal transduction and regulatory pathways that include a receptor tyrosine kinase/Ras/mitogen-activated protein kinase pathway and synthetic multivulva (SynMuv) pathways. Many genes in the SynMuv pathways encode transcription factors including the homologs of mammalian Rb, E2F, and components of the nucleosome-remodeling deacetylase complex. To further elucidate the functions of the SynMuv genes, we performed a genome-wide RNA interference (RNAi) screen to search for genes that antagonize the SynMuv gene activities. Among those that displayed a varying degree of suppression of the SynMuv phenotype, 32 genes are potentially involved in chromatin remodeling (called SynMuv suppressor genes herein). Genetic mutations of two representative genes (zfp-1 and mes-4) were used to further characterize their positive roles in vulval induction and relationships with Ras function. Our analysis revealed antagonistic roles of the SynMuv suppressor genes and the SynMuv B genes in germline-soma distinction, RNAi, somatic transgene silencing, and tissue specific expression of pgl-1 and the lag-2/Delta genes. The opposite roles of these SynMuv B and SynMuv suppressor genes on transcriptional regulation were confirmed in somatic transgene silencing. We also report the identifications of ten new genes in the RNAi pathway and six new genes in germline silencing. Among the ten new RNAi genes, three encode homologs of proteins involved in both protein degradation and chromatin remodeling. Our findings suggest that multiple chromatin remodeling complexes are involved in regulating the expression of specific genes that play critical roles in developmental decisions. In animal cells, DNA and genes are packed into a structure called chromatin. Chromatin-modifying protein complexes play a critical role in the regulation of gene expression. These complexes can alter the chemical and structural properties of the chromosome leading to either the repression or activation of gene expression. How these different complexes coordinate to regulate animal development remains to be explored. Several developmental processes in the nematode Caenorhabditis elegans present excellent model systems to study the functions of chromatin modifications. Using a genome-wide screen, the authors have identified 32 genes that encode potential chromatin-modifying proteins that antagonize the function of another set of transcription regulators including homologs of the mammalian Rb tumor suppressor and components of other chromatin-modifying complexes. The antagonistic roles of these two sets of genes have been observed in a variety of cellular and developmental processes, including organ development and expression of genes in particular tissues. This work indicates that multiple chromatin-modifying complexes are involved in maintaining proper expression of many genes that are critical for precise developmental decisions. Studies on these worm genes should shed light on the roles of the mammalian counterparts in development and related human diseases.