Skip to main content

sRNA regulatory networks

Final Report Summary - MIRNET (sRNA regulatory networks)

1. We exploited the technology we developed for high-throughput miRNA expression profiling to apply it to a number of biological problems. For example, we demonstrated that miRNA expression predicts molecular tumor subtype with great potential for human breast cancer prognostics. Furthermore, we used this technology to work with a number of collaborators to discover new roles for miRNAs in the development of the nervous system, immunology, stem cell and cancer biology in a variety of systems.

2. We took advantage of the miRNA knockout resource I generated as a postdoc to discover new biological functions for miRNAs in C. elegans, e.g. miR-124 and miR-100. In addition, we identified a temperature-sensitive mutant in the miRNA biogenesis pathway that helped us uncover new roles for miRNAs in adult physiology and ageing. This work has uncovered new roles for conserved miRNAs and the miRNA pathway itself that will further our understanding of miRNA biology.

3. We discovered a new enzyme regulating the biogenesis of the let-7 miRNA, a polyU polymerase modifying the 3 end of miRNAs that is conserved in humans. This study revealed a new mechanism by which miRNA biogenesis is controlled. Furthermore, this work identified an enzyme as a negative regulator of the putative tumour suppressor miRNA let-7.

4. We discovered and characterized a germline-specific class of small RNAs (piRNAs) in C. elegans and Xenopus that maintain genome integrity. This work has highlighted how small RNA pathways in the germlines of animals are rapidly evolving to protect the genome from mobile elements. This work also laid the foundation for the genetic and biochemical dissection of the piRNA pathway in C. elegant.

5. In collaboration with the laboratories of Marie-Anne Felix (ENS, Paris) and Dave Wang (Wash U, St. Louis) we characterised the first natural virus of C. elegans, Orsay, a new paradigm for host virus interactions. We were able to demonstrate for the first time that RNAi is an antiviral pathway in nematodes. Positive-strand RNA viruses such as Orsay encompass more than one-third of known virus genera and include many medically and agriculturally relevant human, animal, and plant pathogens. Based on this work we are establishing C. elegans/Orsay as a new animal model of host-virus interaction.

6. We identified the first example of paramutation or stable, transgenerational epigenetic inheritance in animals and identified a nuclear RNAi/chromatin pathway responsible for this phenomenon. This discovery fundamentally changes our understanding of transgenerational epigenetic inheritance as it provides a potential mechanism for a number of such phenomena reported in a wide variety of systems including humans.