RNA interference (RNAi) was recently discovered as a gene-silencing phenomenon initiated by double stranded RNA (dsRNA). While RNAi is widely used as a tool for downregulation of gene expression, we are interested in the endogenous RNAi processes in the nematode C. elegans. The key components of various RNAi-related pathways are short RNAs produced from dsRNA precursors and the ancient Argonaute family proteins that interact with these short RNAs. The focus of our research is on RNAi pathways that lead to transcriptional repression and its accompanying changes in chromatin organization. We are interested in both the mechanisms of RNAi-induced transcriptional silencing and its role in regulation of gene expression during development.

We found that RNAi pathway genes synergize with the Retinoblastoma orthologue lin-35 to repress nuclear divisions in the intestinal cells of C. elegans. The number of nuclei in the intestine increases almost twice when both the RNAi and Rb pathways are inactivated. This excessive division of nuclei requires zfp-1, a C. elegans orthologue of the AF10 oncogene implicated in myeloid leukemias. Cyclin E is one of the target genes controlled by Rb and RNAi pathways that is responsible for the increased nuclei divisions. Our future studies will focus on the molecular mechanisms of transcriptional regulation of the cyclin E gene by Rb, Zfp-1 and endogenous short RNAs.

Selected publications

Grishok, A., and Sharp, P.A. Negative regulation of nuclear divisions in Caenorhabditis elegans by retinoblastoma and RNA interference-related genes. PNAS 102, 17360-17365 (2005).

Grishok, A. RNAi mechanisms in C. elegans (review). FEBS Letters 579, 5932- 5939 (2005).

Grishok, A., Sinskey, J.L. and Sharp, P.A. Transcriptional silencing of a transgene by RNAi in the soma of C. elegans. Genes & Dev 19, 683-696 (2005).

Grishok, A. and Mello, C. C. RNAi (Nematodes: Caenorhabditis elegans) (review). Advances in Genetics 46, 339-360 (2002).

Grishok, A., Pasquinelli, A.E., Conte, D., Li, N., Parrish, S., Ha, I., Baillie, D.L., Fire, A., Ruvkun, G. and Mello, C.C. Genes and Mechanisms Related to RNA Interference Regulate Expression of the Small Temporal RNAs that Control C. elegans Developmental Timing. Cell 106, 23-34 (2001).

Grishok, A., Tabara, H. and Mello, C.C. Genetic Requirements for Inheritance of RNAi in C. elegans. Science 287, 2494-2497 (2000).