C. elegans ISWI and NURF301 antagonize an Rb-like pathway in the determination of multiple cell fates

Area of Science:

• Developmental Biology
• Molecular Biology
• Genetics

Background:

• Class A, B, and C synthetic multivulva (synMuv) genes in C. elegans negatively regulate vulval cell fate.
• Class B and C synMuv proteins are homologs of chromatin-modulating and transcription-influencing proteins found in complexes like Myb-MuvB/dREAM, NuRD, and Tip60/NuA4.

Purpose of the Study:

• To elucidate how chromatin-remodeling activities of synMuv proteins negatively regulate vulval cell-fate decisions.
• To identify genes that suppress the synMuv phenotype.

Main Methods:

• Isolation and characterization of a synMuv phenotype suppressor gene.
• Genetic analysis of the identified suppressor gene (isw-1) and its interaction with other genes (nurf-1, lin-35 Rb, let-60 Ras).
• Assessment of the effects of mutations on synMuv and multivulva phenotypes.

Main Results:

• The suppressor gene encodes the C. elegans homolog of Drosophila ISWI (ISW-1).
• ISW-1, likely part of a Nucleosome Remodeling Factor (NURF) complex with NURF-1, promotes the synMuv phenotype.
• isw-1 and nurf-1 mutations suppress both synMuv and Ras pathway-activated multivulva phenotypes.
• NURF-like complex activity antagonizes transcriptional and chromatin-remodeling activities of synMuv complexes.
• Reduction of isw-1 function suppresses phenotypes associated with lin-35 Rb and let-60 Ras mutations.

Conclusions:

• A NURF-like complex promotes vulval cell fate by opposing the repressive actions of synMuv complexes.
• NURF complex proteins may represent viable targets for cancer therapy, given their role in suppressing tumor-suppressor and oncogene mutations.