The recent discovery of microRNAs (miRNAs) has added a completely new dimension to the control of eukaryotic gene expression. miRNAs are a large class of approximately 22 nucleotide short regulatory RNAs. Approximately 3% of all known human genes encode miRNAs, but very little is known about their biological roles. Our laboratory is interested in understanding how miRNAs contribute to the determination of cell fate, ie the decision to divide, die or differentiate, and how deregulation of miRNAs may contribute to disease, in particular to cancer.

The first miRNA to be identified was the product of the C elegans gene lin-4. Loss of function of lin-4 leads to overproliferation: a stem cell lineage fails to differentiate.

We use the powerful genetics of the nematode Caenorhabditis elegans to study the function of miRNAs. Our starting point is a collection of over one hundred miRNA knockout strains covering the majority of all known miRNA genes in this organism. To place miRNAs into biological networks we combine phenotypic analysis, expression studies, genetic screens and bioinformatics.

We are also interested in the mechanisms by which small RNAs regulate gene expression. We currently use genetic screens, high-throughput sequencing and computational analyses to define how small RNAs mediate post-transcriptional gene silencing (PTGS) and transcriptional gene silencing (TGS).

We recently discovered piRNAs in C elegans, a distinct class of small RNAs that are required for germ stem cell proliferation and germline development. Current work focuses on understanding the biogenesis of these RNAs and how they contribute to germline development.

We have developed an in vivo assay to study miRNA function. Expression of the let-7 miRNA turns a green pharynx red. We use this assay to discover new genes required for miRNA function.

Plain English:
My laboratory is investigating how cells decide to divide to generate all the cells of the body, to become different from each other to form different tissues such as muscle brain or blood. If cells get these decisions wrong, cancer may be the consequence. Our particular focus is a class of small regulatory genes (microRNAs) that act like molecular switches and control many aspects of development and are likely directly involved in human cancer. To better understand the biology of microRNAs we are studying a very simple animal, the roundworm Caenorhabditis elegans, as well as human cancer cells.

Selected publications:

• Das PP, Bagijn MP, Goldstein LD, Woolford JR, Lehrbach NJ, Sapetschnig A, Buhecha HR, Gilchrist MJ, Howe KJ, Stark R, Berezikov E, Ketting RF, Tavaré S, Miska EA (2008) Piwi and piRNAs act upstream of an endogenous siRNA pathway to suppress Tc3 transposon mobility in the Caenorhabditis elegans germline. Mol Cell 31, 79-90

• Choi PS, Zakhary L, Choi WY, Caron S, Alvarez-Saavedra E, Miska EA, McManus M, Harfe B, Giraldez AJ, Horvitz RH, Schier AF, Dulac C. (2008) Members of the miRNA-200 family regulate olfactory neurogenesis. Neuron 57, 41-55.

• Blenkiron C, Goldstein LD, Thorne NP, Spiteri I, Chin SF, Dunning M, Barbosa-Morais NL, Teschendorff A, Green AR, Ellis IO, Tavaré S, Caldas C, Miska EA (2007) MicroRNA expression profiling of human breast cancer identifies new markers of tumour subtype. Genome Biology 8, R214

• Miska EA, Alvarez-Saavedra E, Abbott AL, Lau NC, Hellman AB, Bartel DP, Ambros VR, Horvitz HR (2007) Most Caenorhabditis elegans microRNAs are individually not essential for development or viability. PLoS Genet 3, e215.

piRNAs and Piwi proteins are required to generate endogenous siRNAs to specifically regulate the Tc3 DNA transposon.